Vinyl-phenyl derivatives for inflammation and immune-related uses

ABSTRACT

The invention relates to compounds of structural formula (Ia):  
                 
 
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein X 1 , X 2 , X 3 , X 4 , X 6 , X 10 , R 1 , Y, Z, L, and n are defined herein. These compounds are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/761,875, filed Jan. 25, 2006 and U.S. Provisional Application No.60/762,016, filed on Jan. 25, 2006. The entire teachings of each ofthese applications are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to biologically active chemical compounds, namelyvinyl-phenyl derivatives that may be used for immunosuppression or totreat or prevent inflammatory conditions, allergic disorders and immunedisorders.

BACKGROUND OF THE INVENTION

Inflammation is a mechanism that protects mammals from invadingpathogens. However, while transient inflammation is necessary to protecta mammal from infection, uncontrolled inflammation causes tissue damageand is the underlying cause of many illnesses. Inflammation is typicallyinitiated by binding of an antigen to T-cell antigen receptor. Antigenbinding by a T-cell initiates calcium influx into the cell via calciumion channels, such as Ca²⁺-release-activated Ca²⁺ channels (CRAC).Calcium ion influx in turn initiates a signaling cascade that leads toactivation of these cells and an inflammatory response characterized bycytokine production.

Interleukin 2 (IL-2) is a cytokine that is secreted by T cells inresponse to calcium ion influx into the cell. IL-2 modulatesimmunological effects on many cells of the immune system. For example,it is a potent T cell mitogen that is required for T cell proliferation,promoting their progression from G1 to S phase of the cell cycle; itstimulates the growth of NK cells; and it acts as a growth factor to Bcells and stimulates antibody synthesis.

IL-2, although useful in the immune response, can cause a variety ofproblems. IL-2 damages the blood-brain barrier and the endothelium ofbrain vessels. These effects may be the underlying causes ofneuropsychiatric side effects observed under IL-2 therapy, e.g. fatigue,disorientation and depression. It also alters the electrophysiologicalbehaviour of neurons.

Due to its effects on both T and B cells, IL-2 is a major centralregulator of immune responses. It plays a role in inflammatoryreactions, tumour surveillance, and hematopoiesis. It also affects theproduction of other cytokines, inducing IL-1, TNF-α and TNF-β secretion,as well as stimulating the synthesis of IFN-γ in peripheral leukocytes.

T cells that are unable to produce IL-2 become inactive (anergic). Thisrenders them potentially inert to any antigenic stimulation they mightreceive in the future. As a result, agents which inhibit IL-2 productioncan be used for immunosupression or to treat or prevent inflammation andimmune disorders. This approach has been clinically validated withimmunosuppressive drugs such as cyclosporin, FK506, and RS61443. Despitethis proof of concept, agents that inhibit IL-2 production remain farfrom ideal. Among other problems, efficacy limitations and unwanted sideeffects (including dose-dependant nephrotoxicity and hypertension)hinder their use.

Over production of proinflammatory cytokines other than IL-2 has alsobeen implicated in many autoimmune diseases. For example, Interleukin 5(IL-5), a cytokine that increases the production of eosinophils, isincreased in asthma. Overproduction of IL-5 is associated withaccumulation of eosinophils in the asthmatic bronchial mucosa, a hallmark of allergic inflammation. Thus, patients with asthma and otherinflammatory disorders involving the accumulation of eosinophils wouldbenefit from the development of new drugs that inhibit the production ofIL-5.

Interleukin 4 (IL-4) and interleukin 13 (IL-13) have been identified asmediators of the hypercontractility of smooth muscle found ininflammatory bowel disease and asthma. Thus, patients with athsma andinflammatory bowel disease would benefit from the development of newdrugs that inhibit IL-4 and IL-13 production.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a regulatorof maturation of granulocyte and macrophage lineage population and hasbeen implicated as a key factor in inflammatory and autoimmune diseases.Anti-GM-CSF antibody blockade has been shown to ameliorate autoimmunedisease. Thus, development of new drugs that inhibit the production ofGM-CSF would be beneficial to patients with an inflammatory orautoimmune disease.

There is a continuing need for new drugs which overcome one or more ofthe shortcomings of drugs currently used for immunosuppression or in thetreatment or prevention of inflammatory disorders, allergic disordersand autoimmune disorders. Desirable properties of new drugs includeefficacy against diseases or disorders that are currently untreatable orpoorly treatable, new mechanism of action, oral bioavailability and/orreduced side effects.

SUMMARY OF THE INVENTION

This invention meets the above-mentioned needs by providing certainvinyl-phenyl derivatives that inhibit the activity of CRAC ion channelsand inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α,and IFNγ. These compounds are particularly useful for immunosuppressionand/or to treat or prevent inflammatory conditions, allergic disordersand immune disorders.

In one embodiment, the invention relates to compounds of structuralformula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

-   -   X₁ and X₂ are, independently, CH, CZ, or N;    -   X₃ and X₆ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂;    -   X₄ is CH₂, CHR₂, C(R₂)₂, or CHR₄, provided that when X₃ is NR₂,        X₄ is CHR₄, and provided that not more than one of X₃ or X₆ is        NR₂;    -   L is a linker selected from the group consisting of        —NR₅CR^(a)R^(b)—, —CR^(a)R^(b)NR₅—, —C(O)—, —NR₅—C(O)—,        —C(O)—NR₅—, —C(S)—, —C(NR₈)—, —NR₅—C(S)—, —C(S)—NR₅—,        —NR₅—C(NR₈)—, —C(NR₈)—NR₅—, —NR₅C(O)NR₅—, —NR₅C(S)NR₅—,        —NR₅C(NR₈)NR₅—, —S(O)₂NR₅—, —NR₅S(O)₂—, —NR₅S(O)₂NR₅—,        —NR₅CR^(a)R^(b)NR₅—, —CR^(a)═CR^(b)—, —C≡C—, —N═CR^(a)—,        —CR^(a)═N—, —NR₅—N═CR^(a)—, or —CR^(a)═N—NR₅—;    -   Y is an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted monocyclic aryl, or an optionally substituted        heteroaryl;    -   each Z is independently selected from the group consisting of a        lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower        alkyl sufanyl, cyano, nitro, or lower haloalkoxy;    -   R₁ is H or a substituent, provided that when R₁ is H, X₄ is        CHR₄, and X₃ is NR₂;    -   R₂, for each occurrence is, independently, a substituent;    -   R₄ is a substituent;    -   R^(a) and R^(b), for each occurrence, are independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, halo, —OR₅, —SR₅, —NR₆R₇, —C(O)NR₆R₇, —NR₅C(O)R₅,        —C(O)R₅, —C(O)OR₅, —OC(O)R₅, —C(O)SR₅, —SC(O)R₅, —C(S)NR₆R₇,        —NR₅C(S)R₅, —C(S)R₅, —C(S)OR₅, —OC(S)R₅, —C(S)SR₅, —SC(S)R₅,        —C(NR₈)NR₆R₇, —NR₅C(NR₈)R₅, —C(NR₈)R₅, —C(NR₈)OR₅, —OC(NR₈)R₅,        —C(NR₈)SR₅, —SC(NR₈)R₅, —OC(O)OR₅, —OC(O)NR₆R₇, —NR₅C(O)OR₅,        —NR₅C(O)NR₆R₇, —SC(O)OR₅, —SC(O)NR₆R₇, —SC(O)SR₅, —NR₅C(O)SR₅,        —OC(O)SR₅, —OC(S)OR₅, —OC(S)NR₆R₇, —NR₅C(S)OR₅, —NR₅C(S)NR₆R₇,        —SC(S)OR₅, —SC(S)NR₆R₇, —SC(S)SR₅, —NR₅C(S)SR₅, —OC(S)SR₅,        —OC(NR₈)OR₅, —OC(NR₈)NR₆R₇, —NR₅C(NR₈)OR₅, —NR₅C(NR₈)NR₆R₇,        —SC(NR₈)OR₅, —SC(NR₈)NR₆R₇, —SC(NR₈)SR₅, —NR₅C(NR₈)SR₅, or        —OC(NR₈)SR₅;    -   R₅, for each occurrence, is independently, H, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₆ and R₇, for each occurrence are, independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₆ and R₇ taken together with the nitrogen to which they are        attached are an optionally substituted heterocyclyl or        optionally substituted heteroaryl;    -   R₈, for each occurrence, is independently —H, a halo, an alkyl,        —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or —C(O)NR₆R₇;    -   m is 0, 1, or 2; and    -   n is 0, 1 or 2.

In another embodiment, the invention relates to compounds represented bystructural formula (Ia):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁ and X₂ are, independently, CH, CZ, or N;    -   X₃, X₆ and X₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or        NR₂;    -   X₄ is CH₂, CHR₂, C(R₂)₂, or CHR₄, provided that when X₃ is NR₂,        X₄ is CHR₄, and provided that not more than one of X₃, X₆ or X₁₀        is NR₂;    -   L₁ is a linker selected from the group consisting of —NRC(R)₂—,        —C(R)₂NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —C(S)—, —C(NR₈)—,        —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—, —C(NR₈)—NR—, —NRC(O)NR—,        —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—, —NRS(O)₂NR—,        —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or        —CR═N—NR—;    -   Y is an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted monocyclic aryl, or an optionally substituted        heteroaryl;    -   each Z is independently selected from the group consisting of a        lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower        alkyl sufanyl, cyano, nitro, or lower haloalkoxy;    -   R is H or a lower alkyl;    -   R₁ is H or a substituent, provided that when R₁ is H, X₄ is        CHR₄, and X₃ is NR₂;    -   R₂, for each occurrence is, independently, a substituent,        provided that R₂ is not ═O or ═C(R₂₈)₂;    -   R₄ is a substituent;    -   R₈, for each occurrence, is independently —H, a halo, an alkyl,        —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or —C(O)NR₆R₇;    -   wherein R₂₈, for each occurrence is, independently, H or a        substituent;    -   n is 0, 1 or 2; and    -   q is 0, 1 or 2,    -   provided that when q is 0 or 1, Y is not an optionally        substituted alkyl;    -   provided that when q is 1, Y is not a substituent represented by        the following formula:    -   provided that the compound is not a compound represented by the        following structural formula:    -   wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and    -   t is 0 or 1.

In another embodiment, the invention relates to compounds represented bystructural formula (VII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   L₁ is a linker selected from the group consisting of —NRC(R)₂—,        —C(R)₂NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —C(S)—, —C(NR₈)—,        —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—, —C(NR₈)—NR—, —NRC(O)NR—,        —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—, —NRS(O)₂NR—,        —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or        —CR═N—NR—;    -   R is H or a lower alkyl; and    -   X₁, X₂, X₃, X₄, R₁, R₂, R₈, Y, Z, m and n are defined as for        formula (I).

In one embodiment, the invention relates to compounds represented bystructural formula (X):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   A is —O—, —S—, —NR₁₁—, —CR^(c)═CR^(d)—, —N═CR^(c)—, —CR^(c)═N—,        or —N═N—;    -   W₁ and W₂ are each, independently, CR^(c) or N;    -   Y₁ is an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, or an optionally substituted heteroaryl;    -   L₂ is a linker;    -   R₉ and R₁₀ are each, independently, H, an optionally substituted        alkyl, an optionally substituted alkenyl, or an optionally        substituted alkynyl; or R₉ and R₁₀, together with the carbon        atoms to which they are attached, form an optionally substituted        cycloalkenyl or an optionally substituted heterocyclyl;    -   R₁₁ is H, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, —OR₅, —SR₅, —NR₆R₇, —C(O)NR₆R₇,        —C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅,        —C(S)SR₅, —C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈)OR₅, or —C(NR₈)SR₅;    -   R^(c) and R^(d), for each occurrence, are independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, halo, —OR₅, —SR₅, —NR₆R₇, —C(O)NR₆R₇, —NR₅C(O)R₅,        —C(O)R₅, —C(O)OR₅, —OC(O)R₅, —C(O)SR₅, —SC(O)R₅, —C(S)NR₆R₇,        —NR₅C(S)R₅, —C(S)R₅, —C(S)OR₅, —OC(S)R₅, —C(S)SR₅, —SC(S)R₅,        —C(NR₈)NR₆R₇, —NR₅C(NR₈)R₅, —C(NR₈)R₅, —C(NR₈)OR₅, —OC(NR₈)R₅,        —C(NR₈)SR₅, —SC(NR₈)R₅, —OC(O)OR₅, —OC(O)NR₆R₇, —NR₅C(O)OR₅,        —NR₅C(O)NR₆R₇, —SC(O)OR₅, —SC(O)NR₆R₇, —SC(O)SR₅, —NR₅C(O)SR₅,        'OC(O)SR₅, —OC(S)OR₅, —OC(S)NR₆R₇, —NR₅C(S)OR₅, —NR₅C(S)NR₆R₇,        —SC(S)OR₅, —SC(S)NR₆R₇, —SC(S)SR₅, —NR₅C(S)SR₅, —OC(S)SR₅,        —OC(NR₈)OR₅, —OC(NR₈)NR₆R₇, —NR₅C(NR₈)OR₅, —NR₅C(NR₈)NR₆R₇,        —SC(NR₈)OR₅, —SC(NR₈)NR₆R₇, —SC(NR₈)SR₅, —NR₅C(NR₈)SR₅,        —OC(NR₈)SR₅, —S(O)_(p)R₅, —S(O)_(p)NR₆R₇, —NR₅S(O)_(p)R₅,        —NR₅S(O)NR₆R₇, —S(O)_(p)OR₅, —OS(O)_(p)R₅, or —OS(O)OR₅;    -   p is 1 or 2; and    -   R₅, R₆, R₇, and R₈ are defined as for formula (I).

A compound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof is particularly useful inhibitingimmune cell (e.g., mast cells, T-cells and/or B-cells) activation (e.g.,cytokine production and/or proliferation in response to an antigen; andor mast cell degranulation). In particular, a compound of the inventionor a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof can inhibit the production of certain cytokines that regulateimmune cell activation. For example, a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofcan inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α,INF-γ or combinations thereof. Moreover, a compound of the invention ora pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof can modulate the activity of one or more ion channel involved inactivation of immune cells, such as CRAC ion channels.

In one embodiment, compounds of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof are particularlyuseful for inhibiting mast cell degranulation. Mast cell degranulationhas been implicated in allergic reactions.

A compound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof is particularly useful forimmunosuppression or for treating or preventing inflammatory conditions,allergic disorders, and immune disorders.

The invention also encompasses pharmaceutical compositions comprising acompound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof; and a pharmaceuticallyacceptable carrier or vehicle. These compositions may further compriseadditional agents. These compositions are useful for immunosuppressionand treating or preventing inflammatory conditions, allergic disordersand immune disorders.

The invention further encompasses methods for treating or preventinginflammatory conditions, allergic disorders, and immune disorders,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, or a pharmaceuticalcomposition comprising a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof. These methodsmay also comprise administering to the subject an additional agentseparately or in a combination composition with the compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

The invention further encompasses methods for suppressing the immunesystem of a subject, comprising administering to a subject in needthereof an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, or a pharmaceutical composition comprising a compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof. These methods may also comprise administering to thesubject an additional agent separately or in a combination compositionwith the compound of the invention or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof.

The invention further encompasses methods for inhibiting immune cellactivation, including inhibiting proliferation of T cells and/or Bcells, in vivo or in vitro comprising administering to the cell aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof or apharmaceutical composition comprising a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

The invention further encompasses methods for inhibiting cytokineproduction in a cell (e.g., IL-2, IL4, IL-5, IL-13, GM-CSF, TNF-α,and/or INF-γ production) in vivo or in vitro comprising administering toa cell an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofor a pharmaceutical composition comprising a compound of the inventionor a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

The invention further encompasses methods for modulating ion channelactivity (e.g., CRAC channel activity) in vivo or in vitro comprisingadministering an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofor a pharmaceutical composition comprising a compound of the inventionor a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

All of the methods of this invention may be practice with a compound ofthe invention alone, or in combination with other agents, such as otherimmunosuppressive agents, anti-inflammatory agents, agents for thetreatment of allergic disorders or agents for the treatment of immunedisorders.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term an “aromatic ring” or “aryl” means a monocyclicor polycyclic-aromatic ring or ring radical comprising carbon andhydrogen atoms. Examples of suitable aryl groups include, but are notlimited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, andnaphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted orsubstituted with one or more substituents (including without limitationalkyl (preferably, lower alkyl or alkyl substituted with one or morehalo), hydroxy, alkoxy (preferably, lower alkoxy), alkylsulfanyl, cyano,halo, amino, and nitro. In certain embodiments, the aryl group is amonocyclic ring, wherein the ring comprises 6 carbon atoms.

As used herein, the term “alkyl” means a saturated straight chain orbranched non-cyclic hydrocarbon typically having from 1 to 10 carbonatoms. Representative saturated straight chain alkyls include methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyland n-decyl; while saturated branched alkyls include isopropyl,sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl,3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl,2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Alkylgroups included in compounds of this invention may be optionallysubstituted with one or more substituents. Examples of substituentsinclude, but are not limited to, amino, alkylamino, alkoxy,alkylsulfanyl, oxo, halo, acyl, nitro, hydroxyl, cyano, aryl, alkylaryl,aryloxy, arylsulfanyl, arylamino, carbocyclyl, carbocyclyloxy,carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclylthio, and the like. In addition, anycarbon in the alkyl segment may be substituted with oxygen (═O), sulfur(═S), or nitrogen (═NR²², wherein R²² is —H, an alkyl, acetyl, oraralkyl). Lower alkyls are typically preferred for the compounds of thisinvention.

The term alkylene refers to an alkyl group or a cycloalkyl group thathas two points of attachment to two moieties (e.g., {—CH₂—}, —{CH₂CH₂—},

etc., wherein the brackets indicate the points of attachement). Alkylenegroups may be substituted or unsubstituted with one or moresubstituents.

An aralkyl group refers to an aryl group that is attached to anothermoiety via an alkylene linker. Aralkyl groups can be substituted orunsubstituted with one or more substituents.

The term “alkoxy,” as used herein, refers to an alkyl group which islinked to another moiety though an oxygen atom. Alkoxy groups can besubstituted or unsubstituted with one or more substituents.

The term “alkylsulfanyl,” as used herein, refers to an alkyl group whichis linked to another moiety though a divalent sulfur atom. Alkylsulfanylgroups can be substituted or unsubstituted with one or moresubstituents.

The term “arylsulfanyl,” as used herein, refers to an aryl group whichis linked to another moiety though a divalent sulfur atom. Arylsulfanylgroups can be substituted or unsubstituted with one or moresubstituents.

The term “alkyl ester” as used herein, refers to a group represented bythe formula —C(O)OR₃₂, wherein R₃₂ is an alkyl group. A lower alkylester is a group represented by the formula —C(O)OR₃₂, wherein R₃₂ is alower alkyl group.

The term “heteroalkyl,” as used herein, refers to an alkyl group whichhas one or more carbons in the alkyl chain replaced with an —O—, —S— or—NR₂₇—, wherein R₂₇ is H or a lower alkyl. Heteroalkyl groups can besubstituted or unsubstituted with one or more substituents.

The term “alkylamino,” as used herein, refers to an amino group in whichone hydrogen atom attached to the nitrogen has been replaced by an alkylgroup. The term “dialkylamino,” as used herein, refers to an amino groupin which two hydrogen atoms attached to the nitrogen have been replacedby alkyl groups, in which the alkyl groups can be the same or different.Alkylamino groups and dialkylamino groups can be substituted orunsubstituted with one or more substituents.

As used herein, the term “alkenyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at least one carbon-carbon double bond. Representative straightchain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl,isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl and the like. Alkenyl groups can be substituted orunsubstituted with one or more substituents.

As used herein, the term “alkynyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at lease one carbon-carbon triple bond. Representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl,-1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl,8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl and the like. Alkynyl groupscan be substituted or unsubstituted with one or more substituents.

As used herein, the term “cycloalkyl” means a saturated, mono- orpolycyclic alkyl radical typically having from 3 to 14 carbon atoms.Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly,decahydronaphthyl, octahydropentalene, bicycle[1.1.1]pentanyl, and thelike. Cycloalkyl groups can be substituted or unsubstituted with one ormore substituents.

As used herein, the term “cycloalkenyl” means a cyclic non-aromaticalkenyl radical having at least one carbon-carbon double bond in thecyclic system and typically having from 5 to 14 carbon atoms.Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl,cyclodecadienyl and the like. Cycloalkenyl groups can be substituted orunsubstituted with one or more substituents.

As used herein, the term “heterocyclyl” means a monocyclic or polycyclicheterocyclic ring (typically having 3- to 14-members) which is either asaturated ring or an unsaturated non-aromatic ring. A 3-memberedheterocyclyl can contain up to 3 heteroatoms, and a 4- to 14-memberedheterocyclyl can contain from 1 to about 8 heteroatoms. Each heteroatomis independently selected from nitrogen, which can be quaternized;oxygen; and sulfur, including sulfoxide and sulfone. The heterocyclylmay be attached via any heteroatom or carbon atom. Representativeheterocyclyls include morpholinyl, thiomorpholinyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 4H-pyranyl,tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like. A heteroatom may be substitutedwith a protecting group known to those of ordinary skill in the art, forexample, the hydrogen on a nitrogen may be substituted with atert-butoxycarbonyl group. Furthermore, the heterocyclyl may beoptionally substituted with one or more substituents (including withoutlimitation a halo, an alkyl, a haloalkyl, or aryl). Only stable isomersof such substituted heterocyclic groups are contemplated in thisdefinition.

As used herein, the term “heteroaromatic” or “heteroaryl” means amonocyclic or polycyclic heteroaromatic ring (or radical thereof)comprising carbon atom ring members and one or more heteroatom ringmembers (such as, for example, oxygen, sulfur or nitrogen). Typically,the heteroaromatic ring has from 5 to about 14 ring members in which atleast 1 ring member is a heteroatom selected from oxygen, sulfur andnitrogen. In another embodiment, the heteroaromatic ring is a 5 or 6membered ring and may contain from 1 to about 4 heteroatoms. In anotherembodiment, the heteroaromatic ring system has a 7 to 14 ring membersand may contain from 1 to about 7 heteroatoms. Representativeheteroaryls include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl,imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl,thiadiazolyl, pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl,benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl,tetrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl,azaindolyl, imidazopyridyl, qunizaolinyl, purinyl,pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl or benzo(b)thienyl and thelike. Heteroaryl groups may be optionally substituted with one or moresubstituents

A heteroaralkyl group refers to a heteroaryl group that is attached toanother moiety via an alkylene linker. Heteroaralkyl groups can besubstituted or unsubstituted with one or more substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

As used herein, the term “haloalkyl” means an alkyl group in which oneor more —H is replaced with a halo group. Examples of haloalkyl groupsinclude —CF₃, —CHF₂, —CCl₃, —CH₂CH₂Br, —CH₂CH(CH₂CH₂Br)CH₃, —CHlCH₃, andthe like.

As used herein, the term “haloalkoxy” means an alkoxy group in which oneor more —H is replaced with a halo group. Examples of haloalkoxy groupsinclude —OCF₃ and —OCHF₂.

A “linker,” as used herein, means a diradical having from 1-6 atoms incontiguous linear connectivity that covalently connects the Y₁ group ofa compound of this invention to ring A, as illustrated in formula (X).The atoms of the linker in contiguous linear connectivity may beconnected by saturated or unsaturated covalent bonds. Linker include,but are not limited to, diradicals of alkyl, alkenyl, alkynyl,heteroalkyl, carbonyl, thiocarbonyl, amide, thioamide, ester, imino,ureido, guanadino, hydrazinyl, and sulfonylamino.

The term “contiguous linear connectivity” means connected together so asto form an uninterrupted linear array or series of atoms. For example, alinker of the compounds described herein having a specified number ofatoms in contiguous linear connectivity has at least that number ofatoms connected together so as to form an uninterrupted chain, but mayalso include additional atoms that are not so connected (e.g., branchesor atoms contained within a ring system).

The terms “bioisostere” and “bioisosteric replacement” have the samemeanings as those generally recognized in the art. Bioisosteres areatoms, ions, or molecules in which the peripheral layers of electronscan be considered substantially identical. The term bioisostere isusually used to mean a portion of an overall molecule, as opposed to theentire molecule itself. Bioisosteric replacement involves using onebioisostere to replace another with the expectation of maintaining orslightly modifying the biological activity of the first bioisostere. Thebioisosteres in this case are thus atoms or groups of atoms havingsimilar size, shape and electron density. Preferred bioisosteres ofesters, amides or carboxylic acids are compounds containing two sitesfor hydrogen bond acceptance. In one embodiment, the ester, amide orcarboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring,such as an optionally substituted 1H-imidazolyl, an optionallysubstituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or an optionallysubstituted [1,2,4]oxadiazolyl.

As used herein, the terms “subject”, “patient” and “animal”, are usedinterchangeably and include, but are not limited to, a cow, monkey,horse, sheep, pig, mini pig, chicken, turkey, quail, cat, dog, mouse,rat, rabbit, guinea pig and human. The preferred subject, patient oranimal is a human.

As used herein, the term “lower” refers to a group having up to fourcarbon atoms. For example, a “lower alkyl” refers to an alkyl radicalhaving from 1 to 4 carbon atoms, and a “lower alkenyl” or “loweralkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4carbon atoms, respectively. A lower alkoxy or a lower alkylsulfanylrefers to an alkoxy or an alkylsulfanyl having from 1 to 4 carbon atoms.Lower substituents are typically preferred.

Where a particular substituent, such as an alkyl substituent, occursmultiple times in a given structure or moeity, the identity of thesubstitutent is independent in each case and may be the same as ordifferent from other occurrences of that substituent in the structure ormoiety. Furthermore, individual substituents in the specific embodimentsand exemplary compounds of this invention are preferred in combinationwith other such substituents in the compounds of this invention, even ifsuch individual substituents are not expressly noted as being preferredor not expressly shown in combination with other substituents.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Suitable substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino,dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groupsinclude any substituent which will form a stable compound of theinvention. Examples of substituents for an alkyl, alkoxy, alkylsulfanyl,alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkylinclude an alkyl, an alkoxy, an alkylsulfanyl, an alkylamino, adialkylamino, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aheterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, ahaloalkyl, —C(O)NR₂₃R₂₄, —NR₂₅C(O)R₂₆, halo, —OR₂₅, cyano, nitro,haloalkoxy, —C(O)R₂₅, —NR₂₃R₂₄, —SR₂₅, —C(O)OR₂₅, —OC(O)R₂₅,—NR₂₅C(O)NR₂₃ R₂₄, —OC(O)NR₂₃R₂₄, —NR₂₅C(O)OR₂₆, —S(O)_(p)R₂₅, or—S(O)_(p)NR₂₃R₂₄, wherein R₂₃ and R₂₄, for each occurrence are,independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, acycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or aheteraralkyl; or R₂₃ and R₂₄ taken together with the nitrogen to whichthey are attached is a heterocyclyl or a heteroaryl; and R₂₅ and R₂₆ foreach occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl,a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, anaralkyl, or a heteraralkyl;

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R₂₂.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent thenitrogen may be a quaternary nitrogen.

Choices and combinations of substituents and variables envisioned bythis invention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject). Typically, such compounds arestable at a temperature of 40° C. or less, in the absence of excessivemoisture, for at least one week. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as, without limitation, carboxy,hydroxy, and amino moieties) also include protected derivatives thereof.“Protected derivatives” are those compounds in which a reactive site orsites are blocked with one ore more protecting groups. Suitableprotecting groups for carboxy moieties include benzyl, tert-butyl, andthe like. Suitable protecting groups for amino and amido groups includeacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableproetecting groups for hydroxy include benzyl, trimethyl silyl (TMS) andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981,the entire teachings of which are incorporated herein by reference.

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of any one of formulas (I) through (XXVI), orTable 1, or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof and also include protected derivatives thereof.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may only become active upon suchreaction under biological conditions, but they may have activity intheir unreacted forms. Examples of prodrugs contemplated in thisinvention include, but are not limited to, analogs or derivatives ofcompounds of any one of formulas (I) through (XXVI), or Table 1 thatcomprise biohydrolyzable moieties such as biohydrolyzable amides,biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, and biohydrolyzable phosphateanalogues. Other examples of prodrugs include derivatives of compoundsof any one of formulas (I) through (XXVI), or of Table 1 that comprise—NO, —NO₂, —ONO, or —ONO₂ moieties. Prodrugs can typically be preparedusing well-known methods, such as those described by 1 BURGER'SMEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (ManfredE. Wolff ed., 5^(th) ed), the entire teachings of which are incorporatedherein by reference.

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as uptake,duration of action, or onset of action; or 2) is itself biologicallyinactive but is converted in vivo to a biologically active compound.Examples of biohydrolyzable amides include, but are not limited to,lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from an acid and a basic group of one of the compounds of any oneof formulas (I) through (XXVI) or of Table 1. Illustrative saltsinclude, but are not limited, to sulfate, citrate, acetate, oxalate,chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidphosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate,oleate, tannate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of any one of formulas (I) through (XXVI) or Table 1 having anacidic functional group, such as a carboxylic acid functional group, anda pharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)-amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of any one of formulas (I) through (XXVI) orTable 1 having a basic functional group, such as an amino functionalgroup, and a pharmaceutically acceptable inorganic or organic acid.Suitable acids include, but are not limited to, hydrogen sulfate, citricacid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide,hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lacticacid, salicylic acid, tartaric acid, ascorbic acid, succinic acid,maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid,saccharic acid, formic acid, benzoic acid, glutamic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,andp-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more solvent molecules toone or more molecules of a compound of any one of formulas (I) through(XXVI) or Table 1. The term solvate includes hydrates (e.g.,hemi-hydrate, mono-hydrate, dihydrate, trihydrate, tetrahydrate, and thelike).

As used herein, the term “clathrate” means a compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

As used herein, the term “asthma” means a pulmonary disease, disorder orcondition characterized by reversible airway obstruction, airwayinflammation, and increased airway responsiveness to a variety ofstimuli.

“Immunosuppression” refers to impairment of any component of the immunesystem resulting in decreased immune function. This impairment may bemeasured by any conventional means including whole blood assays oflymphocyte function, detection of lymphocyte proliferation andassessment of the expression of T cell surface antigens. The antisheepred blood cell (SRBC) primary (IgM) antibody response assay (usuallyreferred to as the plaque assay) is one specific method. This and othermethods are described in Luster, M. I., Portier, C., Pait, D. G., White,K. L., Jr., Gennings, C., Munson, A. E., and Rosenthal, G. J. (1992).“Risk Assessment in Immunotoxicology I: Sensitivity and Predictabilityof Immune Tests.” Fundam. Appl. Toxicol., 18, 200-210. Measuring theimmune response to a T-cell dependent immunogen is another particularlyuseful assay (Dean, J. H., House, R. V., and Luster, M. I. (2001).“Immunotoxicology: Effects of, and Responses to, Drugs and Chemicals.”In Principles and Methods of Toxicology: Fourth Edition (A. W. Hayes,Ed.), pp. 1415-1450, Taylor & Francis, Philadelphia, Pa.).

The compounds of this invention can be used to treat subjects withimmune disorders. As used herein, the term “immune disorder” and liketerms means a disease, disorder or condition caused by the immune systemof an animal, including autoimmune disorders. Immune disorders includethose diseases, disorders or conditions that have an immune componentand those that are substantially or entirely immune system-mediated.Autoimmune disorders are those wherein the animal's own immune systemmistakenly attacks itself, thereby targeting the cells, tissues, and/ororgans of the animal's own body. For example, the autoimmune reaction isdirected against the nervous system in multiple sclerosis and the gut inCrohn's disease. In other autoimmune disorders such as systemic lupuserythematosus (lupus), affected tissues and organs may vary amongindividuals with the same disease. One person with lupus may haveaffected skin and joints whereas another may have affected skin, kidney,and lungs. Ultimately, damage to certain tissues by the immune systemmay be permanent, as with destruction of insulin-producing cells of thepancreas in Type 1 diabetes mellitus. Specific autoimmune disorders thatmay be ameliorated using the compounds and methods of this inventioninclude without limitation, autoimmune disorders of the nervous system(e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathiessuch as Guillain-Barré, and autoimmune uveitis), autoimmune disorders ofthe blood (e.g., autoimmune hemolytic anemia, pernicious anemia, andautoimmune thrombocytopenia), autoimmune disorders of the blood vessels(e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides suchas Wegener's granulomatosis, and Behcet's disease), autoimmune disordersof the skin (e.g., psoriasis, dermatitis herpetiformis, pemphigusvulgaris, and vitiligo), autoimmune disorders of the gastrointestinalsystem (e.g., Crohn's disease, ulcerative colitis, primary biliarycirrhosis, and autoimmune hepatitis), autoimmune disorders of theendocrine glands (e.g., Type 1 or immune-mediated diabetes mellitus,Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis andorchitis, and autoimmune disorder of the adrenal gland); and autoimmunedisorders of multiple organs (including connective tissue andmusculoskeletal system diseases) (e.g., rheumatoid arthritis, systemiclupus erythematosus, scleroderma, polymyositis, dermatomyositis,spondyloarthropathies such as ankylosing spondylitis, and Sjogren'ssyndrome). In addition, other immune system mediated diseases, such asgraft-versus-host disease and allergic disorders, are also included inthe definition of immune disorders herein. Because a number of immunedisorders are caused by inflammation, there is some overlap betweendisorders that are considered immune disorders and inflammatorydisorders. For the purpose of this invention, in the case of such anoverlapping disorder, it may be considered either an immune disorder oran inflammatory disorder. “Treatment of an immune disorder” hereinrefers to administering a compound or a composition of the invention toa subject, who has an immune disorder, a symptom of such a disease or apredisposition towards such a disease, with the purpose to cure,relieve, alter, affect, or prevent the autoimmune disorder, the symptomof it, or the predisposition towards it.

As used herein, the term “allergic disorder” means a disease, conditionor disorder associated with an allergic response against normallyinnocuous substances. These substances may be found in the environment(such as indoor air pollutants and aeroallergens) or they may benon-environmental (such as those causing dermatological or foodallergies). Allergens can enter the body through a number of routes,including by inhalation, ingestion, contact with the skin or injection(including by insect sting). Many allergic disorders are linked toatopy, a predisposition to generate the allergic antibody IgE. BecauseIgE is able to sensitize mast cells anywhere in the body, atopicindividuals often express disease in more than one organ. For thepurpose of this invention, allergic disorders include anyhypersensitivity that occurs upon re-exposure to the sensitizingallergen, which in turn causes the release of inflammatory mediators.Allergic disorders include without limitation, allergic rhinitis (e.g.,hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitismedia, drug reactions, insect sting reactions, latex reactions,conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions,atopic dermatitis, asthma and food allergies.

The compounds of this invention can be used to prevent or to treatsubjects with inflammatory disorders. As used herein, an “inflammatorydisorder” means a disease, disorder or condition characterized byinflammation of body tissue or having an inflammatory component. Theseinclude local inflammatory responses and systemic inflammation. Examplesof such inflammatory disorders include: transplant rejection, includingskin graft rejection; chronic inflammatory disorders of the joints,including arthritis, rheumatoid arthritis, osteoarthritis and bonediseases associated with increased bone resorption; inflammatory boweldiseases such as ileitis, ulcerative colitis, Barrett's syndrome, andCrohn's disease; inflammatory lung disorders such as asthma, adultrespiratory distress syndrome, and chronic obstructive airway disease;inflammatory disorders of the eye including corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis;chronic inflammatory disorders of the gums, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney including uremic complications, glomerulonephritis and nephrosis;inflammatory disorders of the skin including sclerodermatitis, psoriasisand eczema; inflammatory diseases of the central nervous system,including chronic demyelinating diseases of the nervous system, multiplesclerosis, AIDS-related neurodegeneration and Alzheimer's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis and viral orautoimmune encephalitis; autoimmune disorders, immune-complexvasculitis, systemic lupus and erythematodes; systemic lupuserythematosus (SLE); and inflammatory diseases of the heart such ascardiomyopathy, ischemic heart disease hypercholesterolemia,atherosclerosis; as well as various other diseases with significantinflammatory components, including preeclampsia; chronic liver failure,brain and spinal cord trauma, and cancer. There may also be a systemicinflammation of the body, exemplified by gram-positive or gram negativeshock, hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,e.g., by a chemotherapeutic agent used in cancer chemotherapy.“Treatment of an inflammatory disorder” herein refers to administering acompound or a composition of the invention to a subject, who has aninflammatory disorder, a symptom of such a disorder or a predispositiontowards such a disorder, with the purpose to cure, relieve, alter,affect, or prevent the inflammatory disorder, the symptom of it, or thepredisposition towards it.

An “effective amount” is the quantity of compound in which a beneficialoutcome is achieved when the compound is administered to a subject oralternatively, the quantity of compound that possess a desired activityin-vivo or in-vitro. In the case of inflammatory disorders andautoimmune disorders, a beneficial clinical outcome includes reductionin the extent or severity of the symptoms associated with the disease ordisorder and/or an increase in the longevity and/or quality of life ofthe subject compared with the absence of the treatment. The preciseamount of compound administered to a subject will depend on the type andseverity of the disease or condition and on the characteristics of thesubject, such as general health, age, sex, body weight and tolerance todrugs. It will also depend on the degree, severity and type ofinflammatory disorder, autoimmune disorder, allergic disorder, or thedegree of immunosuppression sought. The skilled artisan will be able todetermine appropriate dosages depending on these and other factors.Effective amounts of the disclosed compounds typically range betweenabout 1 mg/mm² per day and about 10 grams/mm² per day, and preferablybetween 10 mg/mm² per day and about 1 gram/mm².

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to this invention, the chemical structuresdepicted herein, including the compounds of this invention, encompassall of the corresponding compounds' enantiomers and stereoisomers, thatis, both the stereomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric,diastereomeric, and geometric isomeric mixtures. In some cases, oneenantiomer, diastereomer, or geometric isomer will possess superioractivity or an improved toxicity or kinetic profile compared to others.In those cases, such enantiomers, diastereomers, and geometric isomersof a compound of this invention are preferred.

The term “inhibit production of IL-2” and like terms means inhibitingIL-2 synthesis (e.g. by inhibiting transcription (mRNA expression), ortranslation (protein expression)) and/or inhibiting IL-2 secretion in acell that has the ability to produce and/or secrete IL-2 (e.g., Tlymphocyte). Likewise, the term “inhibiting production of IL-4, IL-5,IL-13, GM-CSF, TNF-α or INF-γ means inhibiting the synthesis (e.g. byinhibiting transcription, or translation) and/or inhibiting thesecretion in a cell that has the ability to produce and/or secrete thesecytokines.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably. more than about 90% by weight, even more preferably morethan about 95% by weight, and most preferably more than about 97% byweight of the compound.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to all chiral centersin the molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of any one of formulas(I) through (XXVI) or Table 1.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

When administered to a patient, e.g., to a non-human animal forveterinary use or for improvement of livestock, or to a human forclinical use, the compounds of the invention are typically administeredin isolated form or as the isolated form in a pharmaceuticalcomposition. As used herein, “isolated” means that the compounds of theinvention are separated from other components of either (a) a naturalsource, such as a plant or cell, preferably bacterial culture, or (b) asynthetic organic chemical reaction mixture. Preferably, viaconventional techniques, the compounds of the invention are purified. Asused herein, “purified” means that when isolated, the isolate containsat least 95%, preferably at least 98%, of a single compound of theinvention by weight of the isolate.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

Specific Embodiments

The invention relates to compounds and pharmaceutical compositions thatare particularly useful for immunosuppression or to treat or preventinflammatory conditions, immune disorders, and allergic disorders.

In one embodiment, the invention relates to compounds of structuralformula (I):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁ and X₂ are, independently, CH, CZ, or N;    -   X₃ and X₆ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂;    -   X₄ is CH₂, CHR₂, C(R₂)₂, or CHR₄, provided that when X₃ is NR₂,        X₄ is CHR₄, and provided that not more than one of X₃ or X₆ is        NR₂;    -   L is a linker selected from the group consisting of        —NR₅CR^(a)R^(b)—, —CR^(a)R^(b)NR₅—, —C(O)—, —NR₅—C(O)—,        —C(O)—NR₅—, —C(S)—, —C(NR₈)—, —NR₅—C(S)—, —C(S)—NR₅—,        —NR₅—C(NR₈)—, —C(NR₈)—NR₅—, —NR₅C(O)NR₅—, —NR₅C(S)NR₅—,        —NR₅C(NR₈)NR₅—, —S(O)₂NR₅—, —NR₅S(O)₂—, —NR₅S(O)₂NR₅—,        —NR₅CR^(a)R^(b)NR₅—, —CR^(a)═CR^(b)—, —C≡C—, —N═CR^(a)—,        —CR^(a)═N—, —NR₅—N═CR^(a)—, or —CR^(a)═N—NR₅—;    -   Y is an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted monocyclic aryl, or an optionally substituted        heteroaryl;    -   each Z is independently selected from the group consisting of a        lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower        alkyl sufanyl, cyano, nitro, or lower haloalkoxy;    -   R₁ is H or a substituent, provided that when R₁ is H, X₄ is        CHR₄, and X₃ is NR₂;    -   R₂, for each occurrence is, independently, a substituent,        provided that R₂ is not ═O or ═C(R₂₈)₂;    -   R₄ is a substituent;    -   R^(a) and R^(b), for each occurrence, are independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, halo, —OR₅, —SR₅, —NR₆R₇, —C(O)NR₆R₇, —NR₅C(O)R₅,        —C(O)R₅, —C(O)OR₅, —OC(O)R₅, —C(O)SR₅, —SC(O)R₅, —C(S)NR₆R₇,        —NR₅C(S)R₅, —C(S)R₅, —C(S)OR₅, —OC(S)R₅, —C(S)SR₅, —SC(S)R₅,        —C(NR₈)NR₆R₇, —NR₅C(NR₈)R₅, —C(NR₈)R₅, —C(NR₈)OR₅, —OC(NR₈)R₅,        —C(NR₈)SR₅, —SC(NR₈)R₅, —OC(O)OR₅, —OC(O)NR₆R₇, —NR₅C(O)OR₅,        —NR₅C(O)NR₆R₇, —SC(O)OR₅, —SC(O)NR₆R₇, —SC(O)SR₅, —NR₅C(O)SR₅,        —OC(O)SR₅, —OC(S)OR₅, —OC(S)NR₆R₇, —NR₅C(S)OR₅, —NR₅C(S)NR₆R₇,        —SC(S)OR₅, —SC(S)NR₆R₇, —SC(S)SR₅, —NR₅C(S)SR₅, —OC(S)SR₅,        —OC(NR₈)OR₅, —OC(NR₈)NR₆R₇, —NR₅C(NR₈)OR₅, —NR₅C(NR₈)NR₆R₇,        —SC(NR₈)OR₅, —SC(NR₈)NR₆R₇, —SC(NR₈)SR₅, —NR₅C(NR₈)SR₅, or        —OC(NR₈)SR₅;    -   R₅, for each occurrence, is independently, H, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;

R₆ and R₇, for each occurrence are, independently, H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₆ and R₇ taken together with the nitrogen to whichthey are attached are an optionally substituted heterocyclyl oroptionally substituted heteroaryl;

-   -   R₈, for each occurrence, is independently —H, a halo, an alkyl,        —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or —C(O)NR₆R₇;    -   R₂₈, for each occurrence is, independently, H or a substituent;    -   m is 0, 1, or 2; and    -   n is 0, 1 or 2.

In another embodiment, the invention relates to compounds represented bystructural formula (Ia):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁ and X₂ are, independently, CH, CZ, or N;    -   X₃, X₆ and X₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or        NR₂;    -   X₄ is CH₂, CHR₂, C(R₂)₂, or CHR₄, provided that when X₃ is NR₂,        X₄ is CHR₄, and provided that not more than one of X₃, X₆ or X₁₀        is NR₂;    -   L₁ is a linker selected from the group consisting of —NRC(R)₂—,        —C(R)₂NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —C(S)—, —C(NR₈)—,        —NR−C(S)—, —C(S)—NR—, —NR—C(NR₈)—, —C(NR₈)—NR—, —NRC(O)NR—,        —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—, —NRS(O)₂NR—,        —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or        —CR═N—NR—;    -   Y is an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted monocyclic aryl, or an optionally substituted        heteroaryl;    -   each Z is independently selected from the group consisting of a        lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower        alkyl sufanyl, cyano, nitro, or lower haloalkoxy;    -   R is H or a lower alkyl;    -   R₁ is H or a substituent, provided that when R₁ is H, X₄ is        CHR₄, and X₃ is NR₂;    -   R₂, for each occurrence is, independently, a substituent,        provided that R₂ is not ═O or ═C(R₂₈)₂;    -   R₄ is a substituent;    -   R₈, for each occurrence, is independently —H, a halo, an alkyl,        —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or —C(O)NR₆R₇;    -   wherein R₂₈, for each occurrence is, independently, H or a        substituent;    -   n is 0, 1 or 2; and    -   q is 0, 1 or 2,    -   provided that when q is 0 or 1, Y is not an optionally        substituted alkyl;    -   provided that when q is 1, Y is not a substituent represented by        the following formula:    -   provided that the compound is not a compound represented by the        following structural formula:    -   wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and    -   t is 0 or 1.

In another embodiment, the invention relates to compounds represented bystructural formula (II):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein X₁, X₂, X₃, X₄, R₁, R₂, Y, Z, m and n        are defined as for formula (I).

In another embodiment, the invention relates to compounds represented bystructural formula (III):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein X₁, X₂, R₁, R₂, and Y are defined as        for formula (I).

In another embodiment, the invention relates to compounds represented bystructural formula (IV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₅ is CH or N;    -   R₁₂ is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a        lower haloalkoxy; and    -   R₁₃ is H, a halo, a lower alkyl, a lower alkoxy, a haloalky, or        a lower haloalkoxy; and    -   X₁, X₂, R₁, and R₂ are defined as for formula (I).

In another embodiment, the invention relates to compounds represented bystructural formula (V):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein X₁, X₂, R₂, R₄, and Y are defined as        for formula (I).

In another embodiment, the invention relates to compounds represented bystructural formula (VI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, R₂, and R₄ are defined as for formula (I); and    -   X₅, R₁₂ and R₁₃ are defined as for formula (IV).

In another embodiment, the invention relates to compounds represented bystructural formula (VII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   L₁ is a linker selected from the group consisting of —NRC(R)₂—,        —C(R)₂NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —C(S)—, —C(NR₈)—,        —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—, —C(NR₈)—NR—, —NRC(O)NR—,        —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—, —NRS(O)₂NR—,        —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or        —CR═N—NR—;    -   R is H or a lower alkyl; and    -   X₁, X₂, X₃, X₄, R₁, R₂, R₈, Y, Z, m and n are defined as for        formula (I).

In another embodiment, the invention relates to compounds represented bystructural formula (VIII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein X₁, X₂, R₁, R₂, and Y are defined as        for formula (I).

In another embodiment, the invention relates to compounds represented bystructural formula (IX):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, R₁, and R₂ are defined as for formula (I); and    -   X₅, R₁₂ and R₁₃ are defined as for formula (IV).

In another embodiment, the invention relates to compounds represented byformula (XVI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein X₁, X₂, R₁, R₂, and Y are defined as        for formula (I); and    -   L₁ is defined as in formula (Ia).

In another embodiment, the invention relates to compounds represented byformula (XVII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, R₂, and R₂ are defined .as for formula (I); and    -   X₅, R₁₂ and R₁₃ are defined as for formula (IV).

In another embodiment, the invention relates to compounds represented byformula (XVIII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, X₆, R₁, R₂, Y and m are defined as for formula (I); and    -   L₁ is defined as in formula (Ia).

In another embodiment, the invention relates to compounds represented byformula (XIX):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, R₁, and Y are defined as for formula (I); and    -   L₁ is defined as in formula (Ia).

In another embodiment, the invention relates to compounds represented byformula (XX):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, and R₁ are defined as for formula (I); and    -   X₅, R₁₂ and R₁₃ are defined as for formula (IV).

In another embodiment, the invention relates to compounds represented byformula (XXI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, R₁, R₂, and Y are defined as for formula (I); and    -   L₁ is defined as in formula (Ia).

In another embodiment, the invention relates to compounds represented byformula (XXII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, R₁ and R₂ are defined as for formula (I); and    -   X₅, R₁₂ and R₁₃ are defined as for formula (IV).

In another embodiment, the invention relates to compounds represented byformula (XXIII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, R₁, R₂, Y, and m are defined as for formula (I); and    -   L₁ is defined as in formula (Ia).

In another embodiment, the invention relates to compounds represented byformula (XXIV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₁, X₂, and R₁ are defined as for formula (I); and    -   X₅, R₁₂ and R₁₃ are defined as for formula (IV).

In another embodiment, the invention relates to compounds represented bystructural formula (X):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   A is —O—, —S—, —NR₁₁—, —CR^(c)═CR^(d)—, —N═CR^(c)—, —CR^(c)═N—,        or —N═N—;    -   W₁ and W₂ are each, independently, CR^(c) or N;    -   Y₁ is an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, or an optionally substituted heteroaryl;    -   L₂ is a linker;    -   R₉ and R₁₀ are each, independently, H, an optionally substituted        alkyl, an optionally substituted alkenyl, or an optionally        substituted alkynyl; or R₉ and R₁₀, together with the carbon        atoms to which they are attached, form an optionally substituted        cycloalkenyl or an optionally substituted heterocyclyl;    -   R₁₁ is H, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, —OR₅, —SR₅, —NR₆R₇, —C(O)NR₆R₇,        —C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅,        —C(S)SR₅, —C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈)OR₅, or —C(NR₈)SR₅;    -   R^(c) and R^(d), for each occurrence, are independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, halo, —OR₅, —SR₅, —NR₆R₇, —C(O)NR₆R₇, —NR₅C(O)R₅,        —C(O)R₅, —C(O)OR₅, —OC(O)R₅, —C(O)SR₅, —SC(O)R₅, —C(S)NR₆R₇,        —NR₅C(S)R₅, —C(S)R₅, —C(S)OR₅, —OC(S)R₅, —C(S)SR₅, —SC(S)R₅,        —C(NR₈)NR₆R₇, —NR₅C(NR₈)R₅, —C(NR₈)R₅, —C(NR₈)OR₅, —OC(NR₈)R₅,        —C(NR₈)SR₅, —SC(NR₈)R₅, —OC(O)OR₅, —OC(O)NR₆R₇, —NR₅C(O)OR₅,        —NR₅C(O)NR₆R₇, —SC(O)OR₅, —SC(O)NR₆R₇, —SC(O)SR₅, —NR₅C(O)SR₅,        —OC(O)SR₅, —OC(S)OR₅, —OC(S)NR₆R₇, —NR₅C(S)OR₅, —NR₅C(S)NR₆R₇,        —SC(S)OR₅, —SC(S)NR₆R₇, —SC(S)SR₅, —NR₅C(S)SR₅, —OC(S)SR₅,        —OC(NR₈)OR₅, —OC(NR₈)NR₆R₇, —NR₅C(NR₈)OR₅, —NR₅C(NR₈)NR₆R₇,        —SC(NR₈)OR₅, —SC(NR₈)NR₆R₇, —SC(NR₈)SR₅, —NR₅C(NR₈)SR₅,        —OC(NR₈)SR₅, —S(O)_(p)R₅, —S(O)_(p)NR₆R₇, —NR₅S(O)_(p)R₅,        —NR₅S(O)NR₆R₇, —S(O)_(p)OR₅, —OS(O)_(p)R₅, or —OS(O)OR₅;    -   p is 1 or 2; and    -   R₅, R₆, R₇, and R₈ are defined as for formula (I).

In another embodiment, the invention relates to compounds represented bystructural formula (XI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   R₁₄, R₁₅, and R₁₆ are each, independently, an alkyl, an alkenyl;        an alkynyl, an aryl, an aralkyl, a heteroaryl, or a        heteroaralkyl; and    -   A, W₁, W₂, L₂ and Y₁ are defined as for formula (X).

In another embodiment, the invention relates to compounds represented bystructural formula (XII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   R₁₇ is a substituent;    -   k is 0 or an integer from 1 to 9; and    -   A, W₁, W₂, L₂ and Y₁ are defined as for formula (X).

In another embodiment, the invention relates to compounds represented bystructural formula (XIII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   X₉ is CH₂ or CHR₁₇;    -   A, W₁, W₂, L₂ and Y₁ are defined as for formula (X); and    -   R₁₇ is defined as for formula (XII).

In another embodiment, the invention relates to compounds represented bystructural formula (XIV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   R₁₈ is H or a substituent;    -   r is 0, or an integer from 1 to 7;    -   A, W₁, W₂, L₂ and Y₁ are defined as for formula (X); and    -   R₁₇ is defined as for formula (XII).

In another embodiment, the invention relates to compounds represented bystructural formula (XV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   A, W₁, W₂, L₂ and Y₁ are defined as for formula (X);    -   R₁₇ is defined as for formula (XII); and    -   R₁₈ is defined as for formula (XIV).

In another embodiment, the invention relates to compounds represented byformula (XXV):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   A is —O—, —S—, —NR₁₁—, —CR^(c)═CR^(d)—, —N═CR^(c)—, —CR^(c)═N—,        or —N═N—;    -   W₁ and W₂ are each, independently, CR^(c) or N;    -   Y₁ is an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, or an optionally substituted heteroaryl;    -   L₂ is a linker;    -   R₁₁ is H, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, —OR₅, —SR₅, —NR₆R₇, —C(O)NR₆R₇,        —C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅,        —C(S)SR₅, —C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈)OR₅, or —C(NR₈)SR₅;    -   R^(c) and R^(d), for each occurrence, are independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, halo, —OR₅, —SR₅, —NR₆R₇, —C(O)NR₆R₇, —NR₅C(O)R₅,        —C(O)R₅, —C(O)OR₅, —OC(O)R₅, —C(O)SR₅, —SC(O)R₅, —C(S)NR₆R₇,        —NR₅C(S)R₅, —C(S)R₅, —C(S)OR₅, —OC(S)R₅, —C(S)SR₅, —SC(S)R₅,        —C(NR₈)NR₆R₇, —NR₅C(NR₈)R₅, —C(NR₈)R₅, —C(NR₈)OR₅, —OC(NR₈)R₅,        —C(NR₈)SR₅, —SC(NR₈)R₅, —OC(O)OR₅, —OC(O)NR₆R₇, —NR₅C(O)OR₅,        —NR₅C(O)NR₆R₇, —SC(O)OR₅, —SC(O)NR₆R₇, —SC(O)SR₅, —NR₅C(O)SR₅,        —OC(O)SR₅, —OC(S)OR₅, —OC(S)NR₆R₇, —NR₅C(S)OR₅, —NR₅C(S)NR₆R₇,        —SC(S)OR₅, —SC(S)NR₆R₇, —SC(S)SR₅, —NR₅C(S)SR₅, —OC(S)SR₅,        —OC(NR₈)OR₅, —OC(NR₈)NR₆R₇, —NR₅C(NR₈)OR₅, —NR₅C(NR₈)NR₆R₇,        —SC(NR₈)OR₅, —SC(NR₈)NR₆R₇, —SC(NR₈)SR₅, —NR₅C(NR₈)SR₅,        —OC(NR₈)SR₅, —S(O)_(p)R₅, —S(O)_(p)NR₆R₇, —NR₅S(O)_(p)R₅,        —NR₅S(O)NR₆R₇, —S(O)_(p)OR₅, —OS(O)_(p)R₅, or —OS(O)OR₅;    -   R₅, for each occurrence, is independently, H, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₆ and R₇, for each occurrence are, independently, H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₆ and R₇ taken together with the nitrogen to which they are        attached are an optionally substituted heterocyclyl or        optionally substituted heteroaryl;    -   R₈, for each occurrence, is independently —H, a halo, an alkyl,        —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or —C(O)NR₆R₇;    -   R₁₄, R₁₅, and R₁₆ are each, independently, an optionally        substituted alkyl, an optionally substituted cycloalkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted heterocycloalkyl, an        optionally substituted aryl, an optionally substituted aralkyl,        an optionally substituted heteroaryl, or an optionally        substituted heteroaralkyl; and    -   p is 1 or 2, provided that the compound is not a polymer;    -   provided that the compound is not represented by one of the        following formulas:    -   wherein R₃₀ is methyl or benzoyl.

In another embodiment, the invention relates to compounds represented byby formula (XXVI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   R₁₄, R₁₅, R₁₆ are defined as for formula (XXV);    -   X₁, X₂, Z, and n are defined as for formula (I); and    -   Y₃ is an optionally substituted aryl or an optionally        substituted heteroaryl.

In some embodiments of the compounds represented by formula (I), L is—NH—C(O)— or —C(O)—NH—.

In some embodiments of the compounds represented by formula (Ia), (VII),(XVI), (XVIII), (XIX), (XXI), or (XXIII), L₁ is —NH—C(O)— or —C(O)—NH—.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), L₂ is —NH—C(O)— or —C(O)—NH—.

In some embodiments of the compounds represented by formula (I), L is—NH—CH₂— or —CH₂—NH—.

In some embodiments of the compounds represented by formula (Ia), (VII),(XVI), (XVIII), (XIX), (XXI), or (XXIII), L₁ is —NH—CH₂— or —CH₂—NH—.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), L₂ is —NH—CH₂— or —CH₂—NH—.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), L₂ is selected from the groupconsisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—,—C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—, —C(NR₈)—NR—,—NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—, —NRS(O)₂NR—,—NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or —CR═N—NR—;wherein R is H or a lower alkyl.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), L₂ is —NRCH₂—, —CH₂NR—, —C(O)—,—NR—C(O)—, —C(O)—NR—, —C(S)—, —NR—C(S)—, —C(S)—NR—, —NRC(O)NR—,—NRC(S)NR—, —NRS(O)₂—, —NRC(R)₂NR—, —CR═CR—, or —NR—N═CR—.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (VII), or (XXVI), n is 0.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (VII), or (XXVI), n is 1. In one aspect of this embodiment, Z is ahalo.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (VII), or (XXVI), n is 2. In one aspect of this embodiment, Z, foreach occurrence, is, independently, a halo.

In some embodiments of the compounds represented by formula (Ia), (VII),(XVI), (XVIII), (XIX), (XXI), or (XXIII), R is H.

In some embodiments of the compounds represented by formula (Ia), (VII),(XVI), (XVIII), (XIX), (XXI), or (XXIII), R is a lower alkyl, such asmethyl.

In some embodiments of the compounds represented by formula (I), (II),(VII), (XVIII), or (XXIII), m is 0.

In some embodiments of the compounds represented by formula (I), (II),or (VII), m is 0, X₃ is NR₂, and X₄ is CHR₄.

In some embodiments of the compounds represented by formula (I), (II),(VII), (XVIII), or (XXIII), m is 1.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (V), (VII), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVIII), (XIX), (XXI), (XXIII), (XXV), or (XXVI), Y, Y₁, or Y₃ isselected from the group consisting of an optionally substituted phenyl,an optionally substituted pyridyl, an optionally substituted furyl, anoptionally substituted thienyl, an optionally substituted pyrrolyl, anoptionally substituted oxazolyl, an optionally substituted imidazolyl,an optionally substituted indolizinyl, an optionally substitutedthiazolyl, an optionally substituted isoxazolyl, an optionallysubstituted pyrazolyl, an optionally substituted isothiazolyl, anoptionally substituted pyridazinyl, an optionally substitutedpyrimidinyl, an optionally substituted pyrazinyl, an optionallysubstituted triazinyl, an optionally substituted triazolyl, anoptionally substituted thiadiazolyl, an optionally substitutedpyrazinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquniolinyl, an optionally substituted indazolyl, anoptionally substituted benzoxazolyl, an optionally substitutedbenzofuryl, an optionally substituted benzothiazolyl, an optionallysubstituted indolizinyl, an optionally substituted imidazopyridinyl, anoptionally substituted isothiazolyl, an optionally substitutedtetrazolyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzothiazolyl, an optionally substituted benzothiadiazolyl,an optionally substituted benzoxadiazolyl, an optionally substitutedindolyl, an optionally substituted tetrahydroindolyl, an optionallysubstituted azaindolyl, an optionally substituted imidazopyridyl, anoptionally substituted quinazolinyl, an optionally substituted purinyl,an optionally substituted pyrrolo[2,3]pyrimidyl, an optionallysubstituted pyridopyrimidyl, an optionally substitutedpyrazolo[3,4]pyrimidyl or an optionally substituted benzo(b)thienyl.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (V), (VII), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVIII), (XIX), (XXI), (XXIII), (XXV), or (XXVI), Y, Y₁, or Y₃ isan optionally substituted phenyl, an optionally substituted pyridinyl,an optionally substituted [1,2,3]thiadiazolyl, an optionally substitutedthiophenyl, an optionally substituted thiazolyl, an optionallysubstituted isoxazolyl, an optionally substituted pyrazolyl, anoptionally substituted imidazolyl, or an optionally substitutedpyrrolyl.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (V), (VII), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVIII), (XIX), (XXI), (XXIII), (XXV), or (XXVI), Y, Y₁, or Y₃ isan optionally substituted phenyl or an optionally substituted pyridinyl.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (V), (VII), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVIII), (XIX), (XXI), (XXIII), (XXV), or (XXVI), Y, Y₁, or Y₃ isan optionally substituted aryl or an optionally substituted heteroaryl.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (V), (VII), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVIII), (XIX), (XXI), (XXIII), (XXV), or (XXVI), Y, Y₁, or Y₃ isrepresented by one of the following structure:

-   -   wherein:    -   X₅ and X₈ are each, independently, CH or N;    -   X₇ is O or S;    -   R₁₂ is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a        lower haloalkoxy; and    -   R₁₃ is H, a halo, a lower alkyl, a lower alkoxy, a haloalky, or        a lower haloalkoxy.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (V), (VII), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVIII), (XIX), (XXI), (XXIII), or (XXV), Y or Y₁ is anoptionally substituted cycloalkyl. In some embodiments, Y or Y₁ is anoptionally substituted cyclohexyl or an optionally substitutedcyclopentyl.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (V), (VII), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVIII), (XIX), (XXI), (XXIII), or (XXV), Y or Y₁ is anoptionally substituted heterocyclyl, such as an optionally substitutedmorpholinyl, piperadinyl, piperazinyl and the like.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (VII), (VIII), (IX), (XVI), (XVII), (XVIII), (XIX),(XX), (XXI), (XXII), (XXIII), or (XXIV), R₁ is selected from the groupconsisting of is a halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (VII), (VIII), (IX), (XVI), (XVII), (XVIII), (XIX),(XX), (XXI), (XXII), (XXIII), or (XXIV), R₁ is halo, a lower alkyl, alower alkoxy, a haloalkyl, a lower haloalkoxy, or a heteroaryl. In someembodiments, R₁ is a five membered heteroaryl, such as oxazolyl, anisoxazolyl, a thiazolyl, an isothiazolyl, a tetrazolyl, and the like. Insome embodiments, the five membered heteroaryl may be furthersubstituted with a lower alkyl, a halo, a lower alkyl ester, an amide, alower alkyl amide, a lower alkoxy, or a lower haloalkoxy.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (VII), (VIII), (IX), (XVI), (XVII), (XVIII), (XIX),(XX), (XXI), (XXII), (XXIII), or (XXIV), R₁ is H.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (XVI), (XVII),(XVIII), (XXI), (XXII), or (XXIII), R₂, for each occurrence is,independently, a halo, nitro, cyano, a haloalkyl, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,—C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅,—C(S)SR₅, —C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅,—S(O)_(p)NR₆R₇, —P(O)(OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅)(SR₅),—P(S)(OR₅)(SR₅), —P(O)(SR₅)₂, or —P(S)(SR₅)₂.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (XVI), (XVII),(XVIII), (XXI), (XXII), or (XXIII), R₂, for each occurrence is,independently, an optionally substituted oxazolyl, an optionallysubstituted furanyl, an optionally substituted thiophenyl, an optionallysubstituted thiazolyl, an optionally substituted thiadiazolyl, anoptionally substituted triazolyl, an optionally substituted tetrazolyl,an optionally substituted oxadiazolyl, an optionally substitutedisoxazolyl, an optionally substituted isothiazolyl, —C(O)NR₆R₇, —C(O)R₅,—C(O)OR₅, —C(NR₈)NR₆R₇, —C(NR₈)R₅, —S(O)_(p)R₅, or —S(O)_(p)NR₆R₇.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (XVI), (XVII),(XVIII), (XXI), (XXII), or (XXIII), R₂, for each occurrence is,independently, isopropenyl, alkanoyl (e.g. acetyl, propanoyl, butanoyl,pentanoyl, and the like), or alkoxycarbonyl (e.g., ethoxycarbonyl,methoxycarbonyl, and the like).

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (XVI), (XVII),(XVIII), (XXI), (XXII), or (XXIII), R₂, for each occurrence is,independently, an optionally substituted oxazolyl, an optionallysubstituted furanyl, an optionally substituted thiophenyl, an optionallysubstituted thiazolyl, an optionally substituted thiadiazolyl, anoptionally substituted triazolyl, an optionally substituted tetrazolyl,an optionally substituted oxadiazolyl, an optionally substitutedisoxazolyl, or an optionally substituted isothiazolyl.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (VII), (VIII), (IX), (XVI), (XVII), (XVIII), (XXI),(XXII), or (XXIII), R₁ is a halo, a lower alkyl, a lower alkoxy, ahaloalkyl, a lower haloalkoxy, or an optionally substituted heteroaryl;and R₂ , for each occurrence, is, independently, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, —C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅,—C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅, —C(S)SR₅, —C(NR₈)NR₆R₇,—C(NR₈)R₅, —C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅, —S(O)_(p)NR₆R₇,—P(O)(OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅)(SR₅), —P(S)(OR₅)(SR₅), —P(O)(SR₅)₂,or —P(S)(SR₅)₂.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (VII), (VIII), (IX), (XVI), (XVII), (XVIII), (XXI),(XXII), or (XXIII), R₁ is a halo, a lower alkyl, a lower alkoxy, ahaloalkyl, a lower haloalkoxy, or an optionally substituted heteroaryl;and R₂, for each occurrence, is, independently, an optionallysubstituted oxazolyl, an optionally substituted furanyl, an optionallysubstituted thiophenyl, an optionally substituted thiazolyl, anoptionally substituted thiadiazolyl, an optionally substitutedtriazolyl, an optionally substituted tetrazolyl, an optionallysubstituted oxadiazolyl, an optionally substituted isoxazolyl, anoptionally substituted isothiazolyl, —C(O)N R₆R₇, —C(O)R₅, —C(O)OR₅,—C(N R₈)N R₆R₇, —C(NR₈)R₅, —S(O)_(p)R₅, or —S(O)_(p)NR₆R₇.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (VII), (VIII), (IX), (XVI), (XVII), (XVIII), (XXI),(XXII), or (XXIII), R₁ is a halo, a lower alkyl, a lower alkoxy, ahaloalkyl, a lower haloalkoxy, or an optionally substituted heteroaryl;and R₂, for each occurrence, is, independently, isopropenyl, alkanoyl(e.g. acetyl, propanoyl, butanoyl, pentanoyl, and the like), oralkoxycarbonyl (e.g., ethoxycarbonyl, methoxycarbonyl, and the like).

In some embodiments of the compounds represented by formula (I), (Ia),(II), (III), (IV), (VII), (VIII), (IX), (XVI), (XVII), (XVIII), (XXI),(XXII), or (XXIII), R₁ is a halo, a lower alkyl, a lower alkoxy, ahaloalkyl, a lower haloalkoxy, or a heteroaryl; and R₂, for eachoccurrence, is, independently, an optionally substituted oxazolyl, anoptionally substituted furanyl, an optionally substituted thiophenyl, anoptionally substituted thiazolyl, an optionally substitutedthiadiazolyl, an optionally substituted triazolyl, an optionallysubstituted tetrazolyl, an optionally substituted oxadiazolyl, anoptionally substituted isoxazolyl, or an optionally substitutedisothiazolyl.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (V), (VI), or (VII), R₄ is selected from the group consisting ofis a halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (V), (VI), or (VII), R₄ is halo, a lower alkyl, a lower alkoxy, ahaloalkyl, a lower haloalkoxy, or a heteroaryl. In some embodiments, R₄is a five membered heteroaryl, such as oxazolyl, an isoxazolyl, athiazolyl, an isothiazolyl, a tetrazolyl, and the like. In someembodiments, the five membered heteroaryl may be further substitutedwith a lower alkyl, a halo, a lower alkyl ester, an amide, a lower alkylamide, a lower alkoxy, or a lower haloalkoxy.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (V), (VI), or (VII), R₄ is a halo, a lower alkyl, a lower alkoxy,a haloalkyl, a lower haloalkoxy, or an optionally substitutedheteroaryl; and R₂, for each occurrence, is, independently, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, —C(O)NR₆R₇,—C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅, —C(S)SR₅,—C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅,—S(O)_(p)NR₆R₇, —P(O)(OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅)(SR₅),—P(S)(OR₅)(SR₅), —P(O)(SR₅)₂, or —P(S)(SR₅)₂.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (V), (VI), or (VII), R₄ is a halo, a lower alkyl, a lower alkoxy,a haloalkyl, a lower haloalkoxy, or an optionally substitutedheteroaryl; and R₂, for each occurrence, is, independently, anoptionally substituted oxazolyl, an optionally substituted furanyl, anoptionally substituted thiophenyl, an optionally substituted thiazolyl,an optionally substituted thiadiazolyl, an optionally substitutedtriazolyl, an optionally substituted tetrazolyl, an optionallysubstituted oxadiazolyl, an optionally substituted isoxazolyl, anoptionally substituted isothiazolyl, —C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅,—C(NR₈)NR₆R₇, —C(NR₈)R₅, —S(O)_(p)R₅, or —S(O)_(p)NR₆R₇.

In some embodiments of the compounds represented by formula (I), (Ia),(II), (V), (VI), or (VII), R₄ is a halo, a lower alkyl, a lower alkoxy,a haloalkyl, a lower haloalkoxy, or an optionally substitutedheteroaryl; and R₂, for each occurrence, is, independently, isopropenyl,alkanoyl (e.g. acetyl, propanoyl, butanoyl, pentanoyl, and the like), oralkoxycarbonyl (e.g., ethoxycarbonyl, methoxycarbonyl, and the like).

In some embodiments of the compounds represented by formula (I), (Ia),(II), (V), (VI), or (VII), R₄ is a halo, a lower alkyl, a lower alkoxy,a haloalkyl, a lower haloalkoxy, or an optionally substitutedheteroaryl; and R₂, for each occurrence, is, independently, anoptionally substituted oxazolyl, an optionally substituted furanyl, anoptionally substituted thiophenyl, an optionally substituted thiazolyl,an optionally substituted thiadiazolyl, an optionally substitutedtriazolyl, an optionally substituted tetrazolyl, an optionallysubstituted oxadiazolyl, an optionally substituted isoxazolyl, or anoptionally substituted isothiazolyl.

In some embodiments of the compounds represented by formula (IV), (VI),(IX), (XVII), (XX), (XXII), or (XXIV), X₅ is CH and R₁₂ and R₁₃ areeach, independently, a lower alkyl or a halo.

In some embodiments of the compounds represented by formula (IV), (VI),(IX), (XVII), (XX), (XXII), or (XXIV), X₅ is N and R₁₂ and R₁₃ are each,independently, H, a lower alkyl or a halo.

In some embodiments of the compounds represented by formula (I), (Ia),or (XVIII), X₆ is CH₂ or CHR₂.

In some embodiments of the compounds represented by formula (I), (Ia),or (XVIII), X₆ is NR₂.

In some embodiments of the compounds represented by formula (I), (Ia),(II), or (VII), X₃ is CH₂ or CHR₂.

In some embodiments of the compounds represented by formula (I), (Ia),(II), or (VII), X₃ is NR₂.

In some embodiments of the compounds represented by formula (Ia), X₁₀ isCH₂ or CHR₂.

In some embodiments of the compounds represented by formula (Ia), X₁₀ isNR₂.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), ring A is an optionallysubstituted phenyl. In one embodiment, W₁ and W₂ are CH; and A is—CH═CH—.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), ring A is an optionallysubstituted pyridinyl. In one embodiment, W₁ and W₂ are CH; and A is—CH═N— or —N═CH—.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), ring A is an optionallysubstituted pyrazinyl or pyrimidinyl. In one embodiment, one of W₁ or W₂are CH and the other is N; and A is —CH═N— or —N═CH—.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), ring A is an optionallysubstituted pyradazinyl. In one embodiment, W₁ or W₂ are N; and A is—CH═CH—.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), ring A is an optionallysubstituted thiophenyl. In one embodiment, W₁ or W₂ are CH; and A is S.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), ring A is an optionallysubstituted furanyl. In one embodiment, W₁ or W₂ are CH; and A is O.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), ring A is an optionallysubstituted thiazolyl. In one embodiment, one of W₁ or W₂ are CH and theother is N; and A is S.

In some embodiments of the compounds represented by formula (X), (XI),(XII), (XIII), (XIV), (XV), or (XXV), ring A is an optionallysubstituted oxazolyl. In one embodiment, one of W₁ or W₂ are CH and theother is N; and A is O.

In some embodiments of the compounds represented by formula (XI), (XXV),or (XXVI), R₁₄, R₁₅ and R₁₆ are each, independently, a lower alkyl.

In some embodiments of the compounds represented by formula (XI), (XXV),or (XXVI), R₁₄ and R₁₆ are a lower alkyl; and R₁₅ is an optionallysubstituted aryl.

In some embodiments of the compounds represented by formula (X), R₉ andR₁₀, together with the carbon atoms to which they are attached, form anoptionally substituted cycloalkenyl or an optionally substitutedheterocyclyl.

In some embodiments of the compounds represented by formula (XII),(XIII), (XIV), or (XV), R₁₇, for each occurrence, is independently,selected from the group consisting of a halo, nitro, cyano, a haloalkyl,an optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, —C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇,—C(S)R₅, —C(S)OR₅, —C(S)SR₅, —C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈)OR₅,—C(NR₈)SR₅, —S(O)_(p)R₅, —S(O)_(p)NR₆R₇, —P(O)(OR₅)₂, —P(S)(OR₅)₂,—P(O)(OR₅)(SR₅), —P(S)(OR₅)(SR₅), —P(O)(SR₅)₂, or —P(S)(SR₅)₂.

In some embodiments of the compounds represented by formula (XII), k is0, 1, or 2.

In some embodiments of the compounds represented by formula (XIV) or(XV), R₁₈, for each occurrence, is independently, selected from thegroup consisting of H, a halo, nitro, cyano, a haloalkyl, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,—C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅,—C(S)SR₅, —C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅,—S(O)_(p)NR₆R₇, —P(O)(OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅)(SR₅), —P(S)(OR₅)(SR₅), —P(O)(SR₅)₂, or —P(S)(SR₅)₂.

In some embodiments of the compounds represented by formula (XIV), r is0, 1, or 2.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   -   3-Fluoro-N-[4-(2-methyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;    -   3-Methyl-N-[4-(2-methyl-5(R)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;    -   3-Methyl-N-[4-(2-methyl-5(S)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;    -   3-Fluoro-N-[4-(2-methyl-5(R)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;    -   3-Fluoro-N-[4-(2-methyl-5(S)-isopropenyl-cyclohex-1-enyl)-pyridin-2-yl]-isonicotinamide;    -   3-Methyl-N-[4-(2-methyl-5(R)-acetyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;    -   N-[4-(1,4-dimethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-2,6-difluoro-benzamide;    -   5-[4-(2,6-difluoro-benzoylamino)-phenyl]-4-methyl-2,4-dihydro-2H-pyridine-1-carboxylic        acid ethyl ester;    -   N-(4-((S)-5-((R)-1,2-dihydroxypropan-2-yl)-2-methylcyclohex-1-enyl)phenyl)-3-methylisonicotinamide;    -   N-(4-(1,4-dimethyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide;    -   N-(4-(1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl        )phenyl)-2,6-difluorobenzamide;    -   Ethyl        3-(4-(2,6-difluorobenzamido)phenyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate;    -   N-(4-(1,5-Dimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide;    -   Ethyl        4-(4-(2,6-difluorobenzamido)phenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate;    -   2,6-Difluoro-N-(4-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)benzamide;    -   N-(4-Cyclohexenylphenyl)-3-fluoroisonicotinamide;    -   N-(4-(1-benzyl-5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide;    -   N-(4-cyclohexenylphenyl)-3-fluoroisonicotinamide;    -   N-[4-(2-chloro-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;    -   N-[4-(2-hydroxymethyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;    -   N-[4-(2-oxazol-5-yl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;    -   N-[4-(2-oxazol-5-yl-cyclohexen-1-yl)-phenyl]-3-fluoroisonicotinamide;    -   N-[4-(2-methyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;    -   5-Methyl-pyrimidine-4-carboxylic acid        [4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide;    -   4-Methyl-pyrimidine-5-carboxylic acid        [4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide;    -   4-Chloro-thiazole-5-carboxylic acid        [4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide;    -   N-[4-(2-ethyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;    -   2-[4-(2,6-Difluoro-benzoylamino)phenyl]-cyclopent-1-enecarboxylic        acid ethyl ester;    -   2,6-Difluoro-N-[4-(2-hydroxymethyl-cyclopent-1-enyl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(2-formyl-cyclopent-1-enyl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(2-vinyl-cyclopent-1-enyl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(2-oxazol-5-yl-cyclopent-1-enyl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(2-methoxycarbonyl-cyclohept-1-enyl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(2-hydroxymethyl-cyclohept-1-enyl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(2-formyl-cyclohept-1-enyl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(2-oxazol-5-yl-cyclohept-1-enyl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(1-methoxycarbonyl-5-ethoxycarbonyl-2,3,6,7-tetrahydro-1H-azepin-4-yl        )-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(1-methoxycarbonyl-5-vinyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-thiazol-2-yl-        1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-isopropyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   N-[4-(4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;    -   2,6-Difluoro-N-[4-(1-thiazol-2-yl4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;    -   N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;    -   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid        [4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide;    -   N-[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;    -   2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   N-[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide,        hydrochloride;    -   N-[4-(1-benzyloxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;    -   N-{4-[1-(4-nitro-phenyloxycarbonyl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;    -   N-[4-(1-allyloxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;    -   2,6-Difluoro-N-[4-(1-allyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(1-phenyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(1-cyano-3-ethoxycarbonyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;    -   N-[4-(1-cyano-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;    -   2,6-Difluoro-N-[4-(1-cyano-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;    -   N-[4-(1-ethanesulfonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl        )-phenyl]-3-methyl-isonicotinamide;    -   N-[4-(1-phenylsulfonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;    -   2,6-Difluoro-N-[4-(1-acetyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(1-cyclopropylcarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   2,6-Difluoro-N-{4-[1-(pyridine-3-carbonyl)-cyclopropanecarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;    -   N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;    -   N-[4-(1-pyridin-2-yl4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;    -   N-[4-(1-benzooxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;    -   2,6-Difluoro-N-[4-(1-benzooxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   N-[4-(1-cyclopropylmethyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;    -   2,6-Difluoro-N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;    -   2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyridin-2-yl]-benzamide,        hydrochloride;    -   2,6-Difluoro-N-[4-(1-thiocarbamoyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;

N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide,dihydrochloride;

-   -   2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide,        hydrochloride;    -   2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   5-Methyl-pyrimidine-4-carboxylic acid        [4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide;    -   2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-formyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide,        hydrochloride;    -   2,6-Difluoro-N-{4-[1-(4-methyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;    -   5-Methyl-pyrimidine-4-carboxylic acid        {4-[1-(4,5-dimethyl-oxazol-2-yl        )-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-amide;    -   2,6-Difluoro-N-{4-[1-(4,5-dimethyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;    -   2,6-Difluoro-N-[4-(1-pyrimidin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;    -   N-{4-[1-(1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;    -   N-{4-[1-(1-methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;    -   N-{4-[1-(2-methyl-2H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;    -   2,6-Difluoro-N-{4-[1-(2-methyl-2H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;    -   2,6-Difluoro-N-{4-[1-(1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;    -   2,6-Difluoro-N-{4-[1-(1-methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;    -   N-[4-(1-pyrimidin-5-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;    -   2,6-Difluoro-N-[4-(1-thiazol-2-yl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;    -   2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyrimidin-2-yl]-benzamide;    -   2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyrimidin-2-yl]-benzamide;    -   pharmaceutically acceptable salts, solvates, clathrates, or        prodrugs thereof.

In another embodiment, the invention relates to3-fluoro-N-(4-(3-methylbut-2-en-2-yl)phenyl)-isonicotinamide, orpharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   -   N-(4-(1,5-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide;    -   ethyl        4-(4-(2,6-difluorobenzamido)phenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate;        and    -   2,6-difluoro-N-(4-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)benzamide;    -   N-(4-(1-benzyl-5-methyl-1,2,3,6-tetrahydropyridin-4-yl        )phenyl)-2,6-difluorobenzamide; or    -   a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   -   3-methyl-N-(4-(2-methyl-1-phenylprop-1-enyl)phenyl)-isonicotinamide;    -   2,6-Difluoro-N-[4-(2-methyl-1-phenyl-propenyl)-phenyl]-benzamide;    -   2,6-Difluoro-N-{4-[2-methyl-1-(4-methoxy-phenyl)-propenyl]-phenyl}-benzamide;    -   2,6-Difluoro-N-{4-[2-methyl-1-(3-methoxy-phenyl)-propenyl]-phenyl}-benzamide;    -   2,6-Difluoro-N-{4-[2-methyl-1-(2-methoxy-phenyl        )-propenyl]-phenyl}-benzamide;    -   2,6-Difluoro-N-[4-(1,2-dimethyl-3-acetoxy-propenyl)-phenyl]-benzamide,    -   a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof.

In another embodiment, the invention relates to2,6-Difluoro-N-[4-(1,2-dimethyl-3-acetoxy-propenyl)-phenyl]-benzamide,or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

All of the features, specific embodiments and particular substituentsdisclosed herein may be combined in any combination. Each feature,embodiment or substituent disclosed in this specification may bereplaced by an alternative feature, embodiment or substituent servingthe same, equivalent, or similar purpose. In the case of chemicalcompounds, specific values for variables (e.g., values shown in theexemplary compounds disclosed herein) in any chemical formula disclosedherein can be combined in any combination resulting in a stablestructure. Furthermore, specific values (whether preferred or not) forsubstituents in one type of chemical structure may be combined withvalues for other substituents (whether preferred or not) in the same ordifferent type of chemical structure. Thus, unless expressly statedotherwise, each feature, embodiment or substituent disclosed is only anexample of a generic series of equivalent or similar features,embodiments or substituents.

In another embodiment, the invention relates to pharmaceuticalcompositions that comprise a compound of any one of formulas (I) through(XXVI), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, as an active ingredient, and apharmaceutically acceptable carrier or vehicle. The compositions areuseful for immunosuppression or to treat or prevent inflammatoryconditions, allergic conditions or immune disorders.

In another embodiment, the invention relates to methods forimmunosuppression or for treating or preventing inflammatory conditions,immune disorders, or allergic disorders in a patient in need thereofcomprising administering an effective amount of a compound representedby any one of formulas (I) through (XXVI), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, the invention relates to methods forimmunosuppression or for treating or preventing inflammatory conditions,immune disorders, or allergic disorders in a patient in need thereofcomprising administering an effective amount of a pharmaceuticalcomposition that comprises a compound represented by any one of formulas(I) through (XXVI), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof.

In another embodiment, compounds of any one of formulas (I) through(XXVI), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, are particularly useful inhibiting immunecell (e.g., T-cells and/or B-cells) activation (e.g., activation inresponse to an antigen) and/or T cell and/or B cell proliferation.Indicators of immune cell activation include secretion of IL-2 by Tcells, proliferation of T cells and/or B cells, and the like. In oneembodiment, immune cell activation and/or T cell and/or B cellproliferation is inhibited in a mammal (e.g., a human), by administeringto the mammal (e.g., human) a compound of any one of formulas (I)through (XXVI) or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof.

In another embodiment, compounds of of any one of formulas (I) through(XXVI), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, can inhibit the production of certaincytokines that regulate immune cell activation. For example, compoundsof any one of formulas (I) through (XXVI), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, can inhibit the production of IL-2, IL4, IL-5, IL-13, GM-CSF,IFN-γ, TNF-α and combinations thereof. In one embodiment, cytokineproduction is inhibited in a mammal (e.g., a human), by administering tothe mammal (e.g., human) a compound of any one of formulas (I) through(XXVI) or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof.

In another embodiment, compounds of any one of formulas (I) through(XXVI), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, can modulate the activity of one or moreion channel, such as CRAC ion channels, involved in activation of immunecells. In one embodiment, a compound of any one of formulas (I) through(XXVI) or Table 1 can inhibit the influx of calcium ions into an immunecell (e.g., T cells, B cells, and/or mast cells) by inhibiting theaction of CRAC ion channels either directly or indirectly. In general, adecrease in I_(CRAC) current upon contacting a cell with a compound isone indicator that the compound inhibitions CRAC ion channels. I_(CRAC)current can be measured, for example, using a patch clamp technique,which is described in more detail in the examples below. In oneembodiment, a compound of any one of formulas (I) through (XXVI) orTable 1 modulates an ion channel in a mammal (e.g., a human). In oneembodiment, the activity of one or more ion channels is inhibited in amammal (e.g., a human), by administering to the mammal (e.g., human) acompound of any one of formulas (I) through (XXVI) or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, compounds of of any one of formulas (I) through(XXVI), or Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, can inhibit degranulation of mast cell.Inhibition of mast cell degranulation can determined as described in theexperimental section herein or by any method known to those skilled inthe art. In one embodiment, mast cell degranulation is inhibited in amammal (e.g., a human), by administering to the mammal (e.g., human) acompound of any one of formulas (I) through (XXVI) or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

Exemplary Compounds of the Invention

Exemplary compounds of the invention are depicted in Table 1 below.TABLE 1 Compound No. Structure Chemical Name 1

3-Fluoro-N-[4-(2-methyl- cyclohex-1-enyl)-phenyl]- isonicotinamide 2

3-Methyl-N-[4-(2-methyl- 5(R)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide 3

3-Methyl-N-[4-(2-methyl- 5(S)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide 4

3-Fluoro-N-[4-(2-methyl- 5(R)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide 5

3-Fluoro-N-[4-(2-methyl- 5(S)-isopropenyl-cyclohex-1-enyl)-pyridin-2-yl]- isonicotinamide 6

3-Methyl-N-[4-(2-methyl- 5(R)-acetyl-cyclohex-1-enyl)-phenyl]-isonicotinamide 7

N-[4-(1,4-dimethyl-1,2,5,6- tetrahydro-pyridin-3-yl)-phenyl]-2,6-difluoro- benzamide 8

5-[4-(2,6-difluoro- benzoylamino)-phenyl]-4- methyl-2,4-dihydro-2H-pyridine-1-carboxylic acid ethyl ester 9

N-(4-((S)-5-((R)-1,2- dihydroxypropan-2-yl)-2- methylcyclohex-1-enyl)phenyl)-3- methylisonicotinamide 10

N-(4-(1,4-dimethyl-1,2,5,6- tetrahydropyridin-3- yl)phenyl)-2,6-difluorobenzamide 11

N-(4-(1-benzyl-4-methyl- 1,2,5,6-tetrahydropyridin-3- yl)phenyl)-2,6-difluorobenzamide 12

Ethyl 3-(4-(2,6- difluorobenzamido)phenyl)- 4-methyl-5,6-dihydropyridine-1(2H)- carboxylate 13

3-Fluoro-N-(4-(3-methylbut- 2-en-2-yl)phenyl)- isonicotinamide 14

3-Methyl-N-(4-(2-methyl-1- phenylprop-1-enyl)phenyl)- isonicotinamide 15

N-(4-(1,5-Dimethyl-1,2,3,6- tetrahydropyridin-4- yl)phenyl)-2,6-difluorobenzamide 16

Ethyl 4-(4-(2,6- difluorobenzamido)phenyl)- 3-methyl-5,6-dihydropyridine-1(2H)- carboxylate 17

2,6-Difluoro-N-(4-(5-methyl- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)benzamide 18

N-(4-Cyclohexenylphenyl)-3- fluoroisonicotinamide 19

N-(4-(1-benzyl-5-methyl- 1,2,3,6-tetrahydropyridin-4- yl)phenyl)-2,6-difluorobenzamide 20

N-(4-cyclohexenylphenyl)-3- fluoroisonicotinamide 21

N-[4-(2-chloro-cyclohex-1- enyl)-phenyl]-2,6-difluoro- benzamide 22

N-[4-(2-hydroxymethyl- cyclohex-1-enyl)-phenyl]-2,6- difluoro-benzamide23

N-[4-(2-oxazol-5-yl-cyclohex- 1-enyl)-phenyl]-2,6-difluoro- benzamide 24

N-[4-(2-oxazol-5-yl- cyclohexen-1-yl)-phenyl]-3- fluoroisonicotinamide25

N-[4-(2-methyl-cyclohex-1- enyl)-phenyl]-2,6-difluoro- benzamide 26

5-Methyl-pyrimidine-4- carboxylic acid [4-(2-methyl-cyclohex-1-enyl)-phenyl]- amide 27

4-Methyl-pyrimidine-5- carboxylic acid [4-(2-methyl-cyclohex-1-enyl)-phenyl]- amide 28

4-Chloro-thiazole-5- carboxylic acid [4-(2-methyl-cyclohex-1-enyl)-phenyl]- amide 29

N-[4-(2-ethyl-cyclohex-1- enyl)-phenyl]-2,6-difluoro- benzamide 30

2-[4-(2,6-Difluoro- benzoylamino)phenyl]- cyclopent-1-enecarboxylic acidethyl ester 31

2,6-Difluoro-N-[4-(2- hydroxymethyl-cyclopent-1- enyl)-phenyl]-benzamide32

2,6-Difluoro-N-[4-(2-formyl- cyclopent-1-enyl)-phenyl]- benzamide 33

2,6-Difluoro-N-[4-(2-vinyl- cyclopent-1-enyl)-phenyl]- benzamide 34

2,6-Difluoro-N-[4-(2-oxazol- 5-yl-cyclopent-1-enyl)- phenyl]-benzamide35

2,6-Difluoro-N-[4-(2- methoxycarbonyl-cyclohept-1-enyl)-phenyl]-benzamide 36

2,6-Difluoro-N-[4-(2- hydroxymethyl-cyclohept-1- enyl)-phenyl]-benzamide37

2,6-Difluoro-N-[4-(2-formyl- cyclohept-1-enyl)-phenyl]- benzamide 38

2,6-Difluoro-N-[4-(2-oxazol- 5-yl-cyclohept-1-enyl)- benzamide 39

2,6-Difluoro-N-[4-(1- methoxycarboxyl-5- ethoxycarbonyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)- phenyl]-benzamide 40

2,6-Difluoro-N-[4-(1- methoxycarbonyl-5-vinyl- 2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl]- benzamide 41

2,6-Difluoro-N-[4-(1- methoxycarbonyl-4-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin- 3-yl)-phenyl]-benzamide 42

2,6-Difluoro-N-[4-(1- methoxycarbonyl-4- isopropyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]- benzamide 43

N-[4-(4-methyl-1,2,5,6- tetrahydro-pyridin-3-yl)- phenyl]-3-methyl-isonicotinamide 44

2,6-Difluoro-N-[4-(1-thiazol- 2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)- phenyl]-benzamide 45

N-[4-(1-methoxycarbonyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3- fluoro-isonicotinamide 46

N-[4-(1-thiazol-2-yl-4-methyl- 1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro- isonicotinamide 47

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid [4-(1-ethoxycarbonyl-4-methyl- 1,2,5,6-tetrahydro-pyridin-3- yl)-phenyl]-amide48

N-[4-(1-ethoxycarbonyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3- methyl-isonicotinamide 49

2,6-Difluoro-N-[4-(1- methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3- yl)-phenyl]-benzamide 50

N-[4-(1-ethoxycarbonyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3- methyl-isonicotinamide, hydrochloride 51

N-[4-(1-benzyloxycarbonyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3- methyl-isonicotinamide 52

N-{4-[1-(4-nitro- phenyloxycarbonyl)-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro- isonicotinamide 53

N-[4-(1-allyloxycarbonyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro- isonicotinamide 54

2,6-Difluoro-N-[4-(1- allyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4- yl)-phenyl]-benzamide 55

2,6-Difluoro-N-[4-(1- phenyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4- yl)-phenyl]-benzamide 56

2,6-Difluoro-N-[4-(1-cyano-3- ethoxycarbonyl-1,2,5,6-tetrahydro-pyridin-4-yl)- phenyl]-benzamide 57

N-[4-(1-cyano-4-methyl- 1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl- isonicotinamide 58

2,6-Difluoro-N-[4-(1-cyano-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]- benzamide 59

N-[4-(1-thiazol-2-yl-4-methyl- 1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl- isonicotinamide 60

N-[4-(1-ethanesulfonyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3- methyl-isonicotinamide 61

N-[4-(1-phenylsulfonyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3- methyl-isonicotinamide 62

2,6-Difluoro-N-[4-(1-acetyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]- benzamide 63

2,6-Difluoro-N-[4-(1- cyclopropylcarbonyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]- benzamide 64

2,6-Difluoro-N-{4-[1- (pyridine-3-carbonyl)- cyclopropanecarbonyl-4-methyl-1,2,5,6-tetrahydro- pyridin-3-yl]-phenyl}- benzamide 65

N-[4-(1-thiazol-2-yl-4-methyl- 1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro- isonicotinamide 66

N-[4-(1-pyridin-2-yl-4-methyl- 1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro- isonicotinamide 67

N-[4-(1-benzooxazol-2-yl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro- isonicotinamide 68

2,6-Difluoro-N-[4-(1- benzooxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3- yl)-phenyl]-benzamide 69

N-[4-(1-cyclopropylmethyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro- isonicotinamide 70

2,6-Difluoro-N-[4-(1-oxazol- 2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)- phenyl]-benzamide 71

N-[4-(1-oxazol-2-yl-4-methyl- 1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro- isonicotinamide 72

2,6-Difluoro-N-[5-(1-thiazol- 2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)- pyridin-2-yl]-benzamide, hydrochloride 73

2,6-Difluoro-N-[4-(1- thiocarbamoyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3- yl)-phenyl]-benzamide 74

N-[4-(1-thiazol-2-yl-4-methyl- 1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro- isonicotinamide, dihydrochloride 75

2,6-Difluoro-N-[4-(1-thiazol- 2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)- phenyl]-benzamide, hydrochloride 76

2,6-Difluoro-N-[4-(1-thiazol- 2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)- phenyl]-benzamide 77

5-Methyl-pyrimidine-4- carboxylic acid [4-(1-thiazol-2-yl-4-methyl-1,2,5,6- tetrahydro-pyridin-3-yl)- phenyl]-amide 78

2,6-Difluoro-N-[4-(1-thiazol- 2-yl-4-formyl-1,2,5,6-tetrahydro-pyridin-3-yl)- phenyl]-benzamide 79

2,6-Difluoro-N-[4-(1-oxazol- 2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)- phenyl]-benzamide, hydrochloride 80

2,6-Difluoro-N-{4-[1-(4- methyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3- yl]-phenyl}-benzamide 81

5-Methyl-pyrimidine-4- carboxylic acid {4-[1-(4,5-dimethyl-oxazol-2-yl)-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-amide 82

2,6-Difluoro-N-{4-[1-(4,5- dimethyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro- pyridin-3-yl]-phenyl}- benzamide 83

2,6-Difluoro-N-[4-(1- pyrimidin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3- yl)-phenyl]-benzamide 84

N-{4-[1-(1H-tetrazol-5-yl)-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro- isonicotinamide 85

N-{4-[1-(1-methyl-1H- tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3- yl]-phenyl}-3-fluoro- isonicotinamide 86

N-{4-[1-(2-methyl-2H- tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3- yl]-phenyl}-3-fluoro- isonicotinamide 87

2,6-Difluoro-N-{4-[1-(2- methyl-2H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro- pyridin-3-yl]-phenyl}- benzamide 88

2,6-Difluoro-N-{4-[1-(1H- tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3- yl]-phenyl}-benzamide 89

2,6-Difluoro-N-{4-[1-(1- methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro- pyridin-3-yl]-phenyl}- benzamide 90

N-[4-(1-pyrimidin-5-yl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro- isonicotinamide 91

2,6-Difluoro-N-[4-(1-thiazol- 2-yl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)- phenyl]-benzamide 92

2,6-Difluoro-N-[4-(2-methyl- 1-phenyl-propenyl)-phenyl]- benzamide 93

2,6-Difluoro-N-{4-[2-methyl- 1-(4-methoxy-phenyl)-propenyl]-phenyl}-benzamide 94

2,6-Difluoro-N-{4-[2-methyl- 1-(3-methoxy-phenyl)-propenyl]-phenyl}-benzamide 95

2,6-Difluoro-N-{4-[2-methyl- 1-(2-methoxy-phenyl)-propenyl]-phenyl}-benzamide 96

2,6-Difluoro-N-[4-(1,2- dimethyl-3-acetoxy- propenyl)-phenyl]-benzamide97

2,6-Difluoro-N-[5-(1-thiazol- 2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)- pyrimidin-2-yl]-benzamide 98

2,6-Difluoro-N-[5-(1-thiazol- 2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)- pyrimidin-2-yl]-benzamide, hydrochloride 99

N-[4-(2-ethyoxycarbonyl- cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide 100

N-[4-(2-formyl-cyclohex-1- enyl)-phenyl]-2,6-difluoro- benzamide 101

N-[4-(2-vinyl-cyclohex-1- enyl)-phenyl]-2,6-difluoro- benzamide 102

3-Fluoro-N-[4-(2-formyl- cyclohex-1-enyl)-phenyl]- isonicotanimide 103

N-[4-(1-methoxycarbonyl-4- methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3- methyl-isonicotinamide 104

N-[4-(4-methyl-1,2,5,6- tetrahydro-pyridin-3-yl)- phenyl]-3-fluoro-isonicotinamide

Mechanism of Action

Activation of T-lymphocytes in response to an antigen is dependent oncalcium ion oscillations. Calcium ion oscillations in T-lymphocytes aretriggered through stimulation of the T-cell antigen receptor, andinvolve calcium ion influx through the stored-operatedCa²⁺-release-activated Ca²⁺ (CRAC) channel. In addition, antigen induceddegranulation of mast cells has also been shown to be initiated bycalcium ion in flux. Although the molecular structure of the CRAC ionchannel has not been identified, a detailed electrophysiological profileof the channel exist. Thus, modulation (e.g., inhibition) of CRAC ionchannels can be measured by measuring modulation (e.g., inhibition) ofthe I_(CRAC) current. Calcium ion oscillations in T-cells have beenimplicated in the activation of several transcription factors (e.g.,NFAT, Oct/Oap and NFκB) which are critical for T-cell activation (Lewis,Biochemical Society Transactions (2003), 31:925-929, the entireteachings of which are incorporated herein by reference). Withoutwishing to be bound by any theory, it is believed that because thecompounds of the invention inhibit the activity of CRAC ion channels,they inhibit immune cell activation.

Methods of Treatment and Prevention

In accordance with the invention, an effective amount of a compound ofany one of formulas (I) through (XXVI) or Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, and prodrug thereof, or apharmaceutical composition comprising a compound of any one of formulas(I) through (XXVI) or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, and prodrug thereof, is administered to a patient inneed of immunosuppression or in need of treatment or prevention of aninflammatory condition, an immune disorder, or an allergic disorder.Such patients may be treatment naive or may experience partial or noresponse to conventional therapies.

Responsiveness to immunosuppression or of a particular inflammatorycondition, immune disorder, or allergic disorder in a subject can bemeasured directly (e.g., measuring blood levels of inflammatorycytokines (such as IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, IFN-γ and thelike) after administration of a compound of this invention), or can beinferred based on an understanding of disease etiology and progression.The compounds of any one of formulas (I) through (XXVI), or Table 1, orpharmaceutically acceptable salts, solvates, clathrates, and prodrugsthereof can be assayed in vitro or in vivo, for the desired therapeuticor prophylactic activity, prior to use in humans. For example, knownanimal models of inflammatory conditions, immune disorders, or allergicdisorders can be used to demonstrate the safety and efficacy ofcompounds of this invention.

Preparation of Compounds of the Invention

General Coupling Procedure for Boronic Esters

To a solution of Pd(PhCN)₂Cl₂ (767 mg, 2 mmol) and1,4-bis(diphenylphosphino)-butane (dppb) (1.28 g, 3 mmol) in 100 mL oftoluene was added a boronic ester (XXXVII) (22.6 mmol) followed by analkenyl halide or alkenyl triflate (XXXVI) (22.6 mmol), and sodiumcarbonate(3.4 g, 22.6 mmol), followed by 23 mL of water and 2 mL ofmethanol. This mixture was heated to 100° C. and refluxed for 18 hours.After allowing cooling to room temperature, the reaction was quenchedwith water and worked-up with ethyl acetate. The organic solution wasthen filtered through silica gel, evaporated in vacuo to give an aminederivative (XXXVIII) (see Scheme I) that was used without furtherpurification in the next step.

General Procedure for Amide Coupling Reaction

Amine derivative (XXXVIII) (19.2 mmol) was dissolved in methylenechloride and cooled to 0° C. Pyridine (3.87 ml, 48 mmol) was added tothe reaction mixture followed by an acyl chloride (XXXIX) (19.2 mmol).This mixture was allowed to warm to room temperature for 35 minutes atwhich time water was added and the reaction mixture was partitionedbetween the methylene chloride and water layers. The organic layer wascollected and dried over a drying agent such as NaSO₄, thenconcentrated. The product was purified using flash chromatography togive a compound of the invention (XL) (see Scheme II).

Compounds of the invention in which L is —NHC(S)— or —C(S)NH— can beprepared by treating compounds having an amide linker with Lawesson'sreagent.

Compounds of the invention having —CH₂—NH— or —NH—CH₂— linkers can beprepared by contacting compounds having —NHC(S)— or —C(S)NH— linkerswith Raney Ni. Alternatively, compounds of the invention having a—CH₂—NH— or —NH—CH₂— linker can be prepared by reducing a compoundhaving a —C(O)—NH— or —NH—C(O)— linker, respectively, with, for example,sodium borohydride (see U.S. patent application Ser. No. 10/897,681,filed on Jul. 22, 2004, the entire teachings of which are incorporatedherein by reference).

Compounds of the invention having —C(O)— linkers can be prepared by aFriedel-Craft acylation reaction by reacting Compound (XLIII), which isprepared using the boronic acid coupling procedure above, with an acidchloride in the presence of AlCl₃ to form a compound of the inventionhaving a carbonyl linker (XLIV) (see Scheme III).

Compounds of the invention that have —C(S)— linkers can be prepared fromcompounds that have carbonyl linkers by treating them with Lawesson'sreagent or P₂S₅ in pyridine.

Compounds of the invention that have a sulfonamide linker (XLVI) can beprepared by reacting an amine derivative (XXXVIII), prepared by themethod described in Scheme I, with a sulfonyl chloride derivative (XLV)as shown in Scheme IV. Typically, the amine derivative (XXXVIII) isdissolved in a polar solvent, such as an alcohol, and the sulfonylchloride derivative (XLV) is added. The reaction is typically heated toabout 50° C. to about 100° C.

Compounds of the invention having a urea linker (XLVIII) can be preparedby reacting amine derivative (XXXVIII) with an isocyanate (XLVII) asshown in Scheme V. Typically, the amine derivative (XXXVIII) isdissolved in a non-polar, aprotic solvent such as dichloromethane (DCM)to which the isocyanate (XLVII) is added at room temperature. Thereaction is typically stirred for about 5 minutes to about 1 hour togive a compound of the invention having a urea linker (XLVIII)

Compounds of the invention having a thiourea linker (—NHC(S)NH—) can beprepared by treating compounds having a urea linker with Lawesson'sreagent.

Compounds of the invention having a hydrazinyl linker (—NH—N═CH—) can beprepared by adding an aqueous solution of NaNO₂ (1 eq.) to a solution ofamine derivative (XXXVIII) (1 eq.) in concentrated HCl at about 0° C.After the solution is stirred at about 0° C. for about 15 minute toabout 1 hour, then 2.4 eq. of SnCl₂ in concentrated HCl is added, andthe reaction is stirred at about 0° C. for about 1 hour to give ahydrazinium chloride intermediate (XLIX). The hydrazinium chlorideintermediate (XLIX) is dissolved in acetic acid and an alcohol, such asmethanol, and an aldehyde (LI) is added. The reaction is stirred at roomtemperature for about an hour to give a compound of the invention havinga hydrazinyl linker (L) (see Scheme VI).

Compounds of the invention having an amide linker in which the aminegroup is attached to Y (—C(O)NH—) can be prepared by combining ahalo-benzyl chloride or halo-pyridine carbonyl chloride (LII) with anamine derivative (XXVII) in pyridine to form a halo-amide intermediate(XXVIII). The reaction conditions are similar to those described for theamide coupling reaction above. A solution of Pd(PhCN)₂Cl₂ (767 mg, 2mmol) and 1,4-bis(diphenylphosphino)-butane (dppb) (1.28 g, 3 mmol) in100 mL of toluene is prepared. A cycloalkylene boronic acid ester (XXIX)is added to the solution, followed by the halo-amide intermediate(XXVIII) (22.6 mmol), and sodium carbonate (22.6 mmol), followed by 23mL of water and 2 mL of methanol. This mixture was heated to 100° C. andrefluxed for about 18 hours. After allowing cooling to room temperature,the reaction was quenched with water and worked-up with ethyl acetate toform a compound of the invention having a —C(O)NH— linker (XXX) (seeScheme VII).

Compounds of the invention that have a double bond linker can beprepared by heating a mixture of a 4-halo-benzyl halide or ahalomethyl-halo-pyridine (XXXI) and a trialkyl-phosphite, such astriethyl phosphate, in a non-polar, aprotic solvent to form a dialkylphosphate derivative (XXXII). The dialkyl phosphate derivative (XXXII)is then dissolved in a polar, aprotic solvent, such as an ether, andcooled to about −25° C. to about −78° C. and sodium-hexamethyidisilazane(NaHMDS) is added. After about 5 minutes to about 30 minutes an aldehydeis added and the solution is stirred for about 15 minutes to about 1hour then allowed to warm to room temperature. The reaction is quenchedwith an aqueous ammonium chloride solution to form alkene intermediate(XXXIII). Alkene intermediate (XXXIII) is then coupled withcycloalkylene boronic acid ester (XXIX) in a similar manner as describedin Scheme VII to form a compound of the invention that has a double bondlinker (XXXIV) (see Scheme VIII).

Compounds that have an amine linker (XXXV) can be prepared by stirring amixture of amine derivative (XXXVIII) (1 equ.), triphenylbismuthine(III)(1.1-1.5 equ.) and Cu(OAc)₂ (1.1-1.5 equ.) in dichloromethane at roomtemperature for about 2-12 hours (see Scheme IX).

Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions and dosage forms of the invention compriseone or more active ingredients in relative amounts and formulated insuch a way that a given pharmaceutical composition or dosage form can beused for immunosuppression or to treat or prevent inflammatoryconditions, immune disorders, and allergic disorders. Preferredpharmaceutical compositions and dosage forms comprise a compound of anyone of formulas (I) through (XXVI), or Table 1, or a pharmaceuticallyacceptable prodrug, salt, solvate, or clathrate thereof, optionally incombination with one or more additional active agents.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., Remington's Pharmaceutical Sciences(1990)18th ed., Mack Publishing, Easton Pa.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines (e.g., N-desmethylvenlafaxineand N,N-didesmethylvenlafaxine) are particularly susceptible to suchaccelerated decomposition. Consequently, this invention encompassespharmaceutical compositions and dosage forms that contain little, ifany, lactose. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient. Lactose-freecompositions of the invention can comprise excipients that are wellknown in the art and are listed, for example, in the U.S. Pharmocopia(USP) SP (XXI)/NF (XVI). In general, lactose-free compositions compriseactive ingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. Preferredlactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water andheat accelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention comprise acompound of any one of formulas (I) through (XXVI), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofin an amount of from about 1 mg to about 1000 mg, preferably in anamount of from about 50 mg to about 500 mg, and most preferably in anamount of from about 75 mg to about 350 mg. The typical total dailydosage of a compound of any one of formulas (I) through (XXVI), or Table1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof can range from about 1 mg to about 5000 mg per day, preferablyin an amount from about 50 mg to about 1500 mg per day, more preferablyfrom about 75 mg to about 1000 mg per day. It is within the skill of theart to determine the appropriate dose and dosage form for a givenpatient.

Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences (1990) 18th ed., MackPublishing, Easton Pa.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Onespecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103J and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

A particular extended release formulation of this invention comprises atherapeutically or prophylactically effective amount of a compound offormulas (I) through (XXVI), or Table 1, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, or prodrug thereof, inspheroids which further comprise microcrystalline cellulose and,optionally, hydroxypropylmethyl-cellulose coated with a mixture of ethylcellulose and hydroxypropylmethylcellulose. Such extended releaseformulations can be prepared according to U.S. Pat. No. 6,274,171, theentire teachings of which are incorporated herein by reference.

A specific controlled-release formulation of this invention comprisesfrom about 6% to about 40% a compound of any one of formulas (I) through(XXVI), or Table 1 by weight, about 50% to about 94% microcrystallinecellulose, NF, by weight, and optionally from about 0.25% to about 1% byweight of hydroxypropyl-methylcellulose, USP, wherein the spheroids arecoated with a film coating composition comprised of ethyl cellulose andhydroxypropylmethylcellulose.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Transdermal, Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa. and Introduction to Pharmaceutical Dosage Forms(1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels. Further, transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Combination Therapy

The methods for immunosuppression or for treating or preventinginflammatory conditions, allergic disorders, and immune disorders in apatient in need thereof can further comprise administering to thepatient being administered a compound of this invention, an effectiveamount of one or more other active agents. Such active agents mayinclude those used conventionally for immunosuppression or forinflammatory conditions, allergic disorders, or immune disorders. Theseother active agents may also be those that provide other benefits whenadministered in combination with the compounds of this invention. Forexample, other therapeutic agents may include, without limitation,steroids, non-steroidal anti-inflammatory agents, antihistamines,analgesics, immunosuppressive agents and suitable mixtures thereof. Insuch combination therapy treatment, both the compounds of this inventionand the other drug agent(s) are administered to a subject (e.g., humans,male or female) by conventional methods. The agents may be administeredin a single dosage form or in separate dosage forms. Effective amountsof the other therapeutic agents and dosage forms are well known to thoseskilled in the art. It is well within the skilled artisan's purview todetermine the other therapeutic agent's optimal effective-amount range.

In one embodiment of the invention where another therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount when the other therapeuticagent is not administered. In another embodiment, the effective amountof the conventional agent is less than its effective amount when thecompound of this invention is not administered. In this way, undesiredside effects associated with high doses of either agent may beminimized. Other potential advantages (including without limitationimproved dosing regimens and/or reduced drug cost) will be apparent tothose of skill in the art.

In one embodiment relating to autoimmune, allergic and inflammatoryconditions, the other therapeutic agent may be a steroid or anon-steroidal anti-inflammatory agent. Particularly useful non-steroidalanti-inflammatory agents, include, but are not limited to, aspirin,ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam, isoxicam; salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophennol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone and pharmaceutically acceptablesalts thereof and mixtures thereof. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed 1996) and GlenR. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference intheir entireties.

Of particular relevance to allergic disorders, the other therapeuticagent may be an anthihistamine. Useful antihistamines include, but arenot limited to, loratadine, cetirizine, fexofenadine, desloratadine,diphenhydramine, chlorpheniramine, chlorcyclizine, pyrilamine,promethazine, terfenadine, doxepin, carbinoxamine, clemastine,tripelennamine, brompheniramine, hydroxyzine, cyclizine, meclizine,cyproheptadine, phenindamine, acrivastine, azelastine, levocabastine,and mixtures thereof. For a more detailed description ofanthihistamines, see Goodman & Gilman's The Pharmacological Basis ofTherapeutics (2001) 651-57, 10^(th) ed).

Immunosuppressive agents include glucocorticoids, corticosteroids (suchas Prednisone or Solumedrol), T cell blockers (such as cyclosporin A andFK506), purine analogs (such as azathioprine (Imuran)), pyrimidineanalogs (such as cytosine arabinoside), alkylating agents (such asnitrogen mustard, phenylalanine mustard, buslfan, and cyclophosphamide),folic acid antagonsists (such as aminopterin and methotrexate),antibiotics (such as rapamycin, actinomycin D, mitomycin C, puramycin,and chloramphenicol), human IgG, antilymphocyte globulin (ALG), andantibodies (such as anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5,anti-CD7, anti-IL-2 receptor, anti-alpha/beta TCR, anti-ICAM-1,anti-CD20 (Rituxan), anti-IL-12 and antibodies to immunotoxins).

The foregoing and other useful combination therapies will be understoodand appreciated by those of skill in the art. Potential advantages ofsuch combination therapies include a different efficacy profile, theability to use less of each of the individual active ingredients tominimize toxic side effects, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Other Embodiments

The compounds of this invention may be used as research tools (forexample, as a positive control for evaluating other potential CRACinhibitors, or IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, and/or INF-γinhibitors). These and other uses and embodiments of the compounds andcompositions of this invention will be apparent to those of ordinaryskill in the art.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds of the invention. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe purpose and interest of this invention. The following examples areset forth to assist in understanding the invention and should not beconstrued as specifically limiting the invention described and claimedherein. Such variations of the invention, including the substitution ofall equivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulation or minorchanges in experimental design, are to be considered to fall within thescope of the invention incorporated herein.

EXAMPLES

Experimental Rationale

Without wishing to be bound by theory, it is believed that the compoundsof this invention inhibit CRAC ion channels, thereby inhibitingproduction of IL-2 and other key cytokines involved with inflammatory,allergic and immune responses. The examples that follow demonstratethese properties.

Materials and General Methods

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR and ¹³C-NMRspectra were recorded on a Varian 300 MHz NMR spectrometer. Significantpeaks are tabulated in the order: δ (ppm): chemical shift, multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,broad singlet), coupling constant(s) in Hertz (Hz) and number ofprotons.

Patch clamp experiments were performed in the tight-seal whole-cellconfiguration at 21-25° C. High resolution current recordings wereacquired by a computer-based patch clamp amplifier system (EPC-9, HEKA,Lambrecht, Germany). Patch pipettes had resistances between 24 MΩ afterfilling with the standard intracellular solution. Immediately followingestablishment of the whole-cell configuration, voltage ramps of 50-200ms duration spanning the voltage range of −100 to +100 mV were deliveredat a rate of 0.5 Hz over a period of 300-400 seconds. All voltages werecorrected for a liquid junction potential of 10 mV between external andinternal solutions when using glutamate as the intracellular anion.Currents were filtered at 2.9 kHz and digitized at 10 μs intervals.Capacitive currents and series resistance were determined and correctedbefore each voltage ramp using the automatic capacitance compensation ofthe EPC-9. The low resolution temporal development of membrane currentswas assessed by extracting the current amplitude at −80 mV or +80 mVfrom individual ramp current records.

Example 1 Synthesis of Representative Exemplary Compounds of thisInvention

In general, the compounds of the invention can be synthesized usingmethods analogous to those described in U.S. patent application Ser. No.10/897,681 and U.S. Provisional Patent Application Ser. No. 60/611,913,the entire teachings of these patent applications are incorporatedherein by reference.

General Suzuki Coupling Procedure for Boronic Esters:

To a solution of Pd(PhCN)₂Cl₂ (767 mg, 2 mmol) and1,4-bis(diphenylphosphino)-butane (dppb) (1.28 g, 3 mmol) in 100 mL oftoluene was added a boronic ester (XXXVII) (22.6 mmol) followed by analkenyl halide or alkenyl triflate (XXXVI) (22.6 mmol), and sodiumcarbonate (3.4 g, 22.6 mmol), followed by 23 mL of water and 2 mL ofmethanol. This mixture was heated to 100° C. and refluxed for 18 hours.After allowing cooling to room temperature, the reaction was quenchedwith water and worked-up with ethyl acetate. The organic solution wasthen filtered through silica gel, evaporated in vacuo to give an aminederivative (XXXVIII) that was used without further purification in thenext step.

General Procedure for Amide Formation using Acyl Chloride:

An amine derivative (XXXVIII) (19.2 mmol) was dissolved in methylenechloride and cooled to 0° C. Pyridine (3.87 ml, 48 mmol) was added tothe reaction mixture followed by an acyl chloride (XXXIX) (19.2 mmol).This mixture was allowed to warm to room temperature for 35 minutes atwhich time water was added and the reaction mixture was partitionedbetween the methylene chloride and water layers. The organic layer wascollected and dried over a drying agent such as NaSO₃, thenconcentrated. The product was purified using flash chromatography togive a compound of the invention (XL).

Compound 1:3-Fluoro-N-(4-(2-methylcyclohex-1-enyl)phenyl)isonicotinamide

A solution of 2-methylcyclohexanone was cooled to 0° C. Triflicanhydride was added and stirred for 30 minutes, followed bytriethylamine. The reaction became dark and was stirred for another 30minutes. After quenching with sodium bicarbonate aqueous solution, thetriflate was subjected to column chromatography with hexane. The titlecompound was then synthesized from the corresponding vinyl triflate viathe general coupling procedures described above.

¹H NMR (300 MHz, CDCl₃) δ 8.66 (d, J=2.7 Hz, 1H), 8.64 (dd, J=1.2, 4.8Hz, 1H), 8.37 (bd, J=13.2 Hz 1H), 8.03 (dd, J=4.8, 6.6 Hz, 1H), 7.60 (d,J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 2.25-2.2 (m, 2H), 2.12-2.01 (m,2H), 1.75-1.69 (m, 4H), 1.57 (s, 3H) ppm. ESMS calcd. (C19H19FN20):310.1; found: 311.1 (M+H).

Compound 20 was prepared in a similar manner as Compound 1.

Compound 20: N-(4-cyclohexenylphenyl)-3-fluoroisonicotinamide

¹H NMR (300 MHz, CDCl₃) δ 8.63-8.66 (m, 2H), 8.37 (bd, J=12.9 Hz, 1 H),8.03 (t, J=5.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H),6.12-6.18 (m, 1H), 2.36-2.44 (m, 2H), 2.18-2.24 (m, 2H), 1.75-1.81 (m,2H), 1.62-1.69 (m, 2H), ppm.

ESMS calcd. (C18H17FN20): 296.1; found: 297.1 (M+H).

Compound 4:3-Fluoro-N-[4-(2-methyl-5(R)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide

A solution of R-carvone (1 g, 6.66 mmol) in 50 ml tetrohydrofuran (THF)was cooled to −78° C., then L-selectride (7 mL of 1 M solution in THF)was added. The reaction was then stirred for 1.5 hours after whichN-phenylbistriflimide (2.5 g, 6.99 mmol) was added as a solid and thereaction was allowed to warm to room temperature overnight. The reactionwas diluted with hexane and worked up with water and brine solution. Thecolorless oil was purified with chromatography using hexane. Product isnot UV active.

General palladium coupling and amide formation procedures were used toobtain Compound 4.

¹H NMR (300 MHz, CDCl₃) δ 8.64(d, J=1.7, 1H), 8.62 (d, J=5.4 Hz, 1H),8.42 (bd, J=12.6 Hz, 1H), 8.01 (t, J=5.9 Hz, 1H), 7.60 (d, J=6.6 Hz,2H), 7.18 (d, J=6.6 Hz, 1H), 4.74 (s, 2H), 2.38-2.18 (m, 5H), 1.81-1.93(m, 1H), 1.77 (s, 3H), 1.23 (s, 3H) ppm.

ESMS calcd. (C22H23FN2O): 350.2; found: 352.2 (M+H).

Compounds 2, 3, and 5 were synthesized in a similar manner to Compound4.

Compound 2:3-Methyl-N-[4-(2-methyl-5(R)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide

¹H NMR (300 MHz, CDCl₃) δ 8.58(s, 1H), 8.56 (d, J=5.4 Hz, 1H), 7.57 (d,J=8.7 Hz, 2H), 7.48 (bs, 1H), 7.35 (d, J=5.1 Hz, 1H), 7.19 (d, J=8.7 Hz,2H), 4.75 (s, 2H), 2.50 (s, 3H), 2.40-2.13 (m, 5H), 1.81-1.82 (m, 1H),1.77 (s, 3H), 1.59 (s, 3H) ppm.

ESMS calcd. (C23H26N2O): 346.2; found: 347.2 (M+H).

Compound 3:3-Methyl-N-[4-(2-methyl-5(S)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide

¹H NMR (300 MHz, CDCl₃) δ 8.58(s, 1H), 8.56 (d, J=5.4 Hz, 1H), 7.57 (d,J=8.7 Hz, 2H), 7.48 (bs, 1H), 7.35 (d, J=5.1 Hz, 1H), 7.19 (d, J=8.7 Hz,2H), 4.75 (s, 2H), 2.50 (s, 3H), 2.40-2.13 (m, 5H), 1.81-1.82 (m, 1H),1.77 (s, 3H), 1.59 (s, 3H) ppm.

ESMS calcd. (C23H26N2O): 346.2; found: 347.2 (M+H).

Compound 5:3-Fluoro-N-[4-(2-methyl-5(S)-isopropenyl-cyclohex-1-enyl)-pyridin-2-yl]-isonicotinamide

¹H NMR (300 MHz, CDCl₃) δ 8.97(d, J=1.2, 1H), 8.88 (d, J=2.4 Hz, 1H),8.64 (d, J=6.0 Hz, 1H), 8.30 (d, J=8.9 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H),8.01 (dd, J=4.8, 6.0 Hz, 1H), 7.59 (dd, J=2.0, 6.6 Hz, 1H), 4.76 (s,2H), 2.4-2.05 (m, 5H), 1.88-1.81. (m, 1H), 2.69 (s, 3H), 2.60 (s, 3H)ppm.

ESMS calcd. (C₂₁H₂₂FN₃O): 351.2; found: 352.2 (M+H).

Compound 9:N-(4-((S)-5-((R)-1,2-dihydroxypropan-2-yl)-2-methylcyclohex-1-enyl)phenyl)-3-methylisonicotinamide

A solution of Compound 3 (133 mg, 0.383 mmol) in 2:1 isopropylalcoholand water was stirred at room temperature. N-morpholine oxide (40 mg, 1eq.) was added followed by a solution of OsO₄ (3 mol %). The reactionwas stirred for 18 hours, quenched with water and extracted withmethylene chloride.

ESMS calcd. (C23H28N2O3): 380.2; found: 381.3 (M+H).

Compound 6:3-Methyl-N-[4-(2-methyl-5(R)-acetyl-cyclohex-1-enyl)-phenyl]-isonicotinamide

A solution of Compound 9 was dissolved in 2:1 isopropyl alcohol andwater and stirred at room temp. Sodium periodate (1 eq.) was added andthe reaction was stirred overnight, quenched with water and washed withethyl acetate. The organic layer was dried and concentrated to yield38.0 mg Compound 6.

¹H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H), 8.54 (d, J=7.0 Hz, 1H), 7.64 (s,1H), 7.59 (d, J=8.7 Hz, 2H), 7.35 (d, J=5.1 Hz, 1H), 7.18 (d, J=8.7 Hz,2H), 2.80-2.68 (m, 1H), 2.49 (s, 3H), 2.45-2.36 (m, 2H), 2.16-2.21 (m,4H), 1.59 (s, 3H) ppm.

ESMS calcd. (C22H24N2O2): 348.2; found: 349.2 (M+H).

Compound 10:N-(4-(1,4-dimethyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide

Step A: A solution of pyridine (200 mg, 0.62 mmol) was dissolved indichloromethane (1.5 mL). Methyl iodide (3 eq) was added and the roomtemperature solution was stirred for 24 hours. The solid was filteredand washed with cold dichloromethane to give pure3-(4-(2,6-difluorobenzamido)phenyl)-1,4-dimethylpyridinium iodide salt.

¹H NMR (300 MHz, CDCl₃) δ 11.08(s, 1H), 8.93 (s, 1H), 8.83 (d, J=6.6 Hz,1H), 8.08 (d, J=6.3 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.56-7.69 (m, 3H),7.29 (t, J=8.1 Hz, 2H), 4.32 (s, 3H), 2.55 (s, 3H) ppm. ESMS calcd.(C20H17F2N2O+): 339.1; found: 339.3 (M⁺).

Step B: A solution of the above pyridinium salt (crude) in methanol wasadded sodium borohydride (113 mg, 3 eq). This solution was warmed to 35degrees for 5 hours then cooled to room temperature. The methanol wasremoved, water and methylene chloride added, and the reaction waspartitioned between the aqueous and organic layers. The organic layerwas collected, dried and concentrated to give the crude product whichwas purified by column chromatography to yield 150 mg (70% yield) ofCompound 10. ¹H NMR (300 MHz, CDCl₃) δ 8.29 (s, 1H), 7.58 (d, J=8.4,2H), 7.42-7.32 (m, 1H), 7.15 (d, J=8.4, 2H), 6.99-6.61 (m, 2H),3.07-2.04 (m, 2H), 2.58 (t, J=5.9 H), 2.36 (s, 3H), 2.60-2.48 (m, 2H),1.60 (s, 3H) ppm. ESMS calcd. For (C20H20F2N2O): 342.2; found: 343.2.(M+H).

Compounds 11, 15, and 19 were synthesized in a similar manner tocompound 10.

Compound 11:N-(4-(1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide

¹H NMR (300 MHz, CDCl₃) δ 7.97 (s, 1H), 7.57 (d, J=8.1 Hz 2H), 7.23-7.43(m, 8H), 7.15 (d, J=8.1 Hz, 2H), 6.69(t, J=8.1 Hz, 3H), 3.63 (s, 2H),3.15 (d, J=1.8 Hz, 2H), 2.64 (t, J=5.7 Hz, 2H), 2.24-2.31 (m, 2H), 1.61(s, 3H) ppm.

ESMS calcd. (C26H24F2N2O): 418.2; found: 419.2. (M+H).

Compound 15:N-(4-(1,5-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide

ESMS calcd. (C20H20F2N2O): 342.2; found: 343.2. (M+H).

Compound 19:N-(4-(1-benzyl-5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide

ESMS calcd. (C26H24F2N2O): 418.2; found: 419.2. (M+H).

Compound 12: Ethyl3-(4-(2,6-difluorobenzamido)phenyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate

Compound 11 (31 mg, 0.074 mmol) was dissolved in methylene chloride (2mL) at room temperature. Ethyl chloroformate (14 ul, 2 eq) was added tothe solution and it was heated to 110° C. in the microwave for 1 hour.The solvent was removed and the crude mixture was flashed with ethylacetate/hexane to produce 28.4 mg (97% yield) of Compound 12.

¹H NMR (300 MHz, CDCl₃) δ 7.65 (d, J=8.1 Hz, 2H), 7.36-7.48 (m, 1H),7.19 (d, J=8.1 Hz, 2H), 6.997 (t, J=8.1 Hz, 1H), 4.004.20(m, 3H),3.59-3.63 (m, 1H), 2.17-2.20 (m, 3H), 1.63 (s, 3H), 1.26 (t, J=6.3Hz,3H) ppm.

ESMS calcd. (C22H22F2N2O3): 400.2; found: 401.2. (M+H).

Compound 8, 16, and 17 were obtained in a similar manner to Compound 12.

Compound 8: Ethyl3-(4-(2,6-difluorobenzamido)phenyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate

¹H NMR (300 MHz, CDCl₃) δ 7.65 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H)7.36-7.48 (m, 2H), 7.15 (t, J=7.8 Hz, 3H), 6.97 (t, J=8.1 Hz, 3H),4.03-4.13(m, 5H), 3.60 (t, J=5.1 Hz, 3H), 2.17-2.20 (m, 2H), 1.58-1.72(m, 3H), 1.23-1.28 (m, 6H), 0.765 9d, J=6.9 Hz, 3H) ppm. ESMS calcd.(C22H22F2N2O3): 400.2; found: 401.2. (M+H).

Compound 16: Ethyl4-(4-(2,6-difluorobenzamido)phenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate

ESMS calcd. (C22H22F2N2O3): 400.21; found: 401.2. (M+H).

Compound 17:2,6-difluoro-N-(4-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)benzamide

ESMS calcd. (C19H18F2N2O): 328.1; found: 329.1. (M+H).

Compounds 13 and 14 were synthesized via general coupling procedure forboronic esters followed by general amide formation from amine proceduredescribed thereinbefore beginning with the corresponding vinyl bromideor vinyl trilfate.

Compound 13: 3-Fluoro-N-(4-(3-methylbut-2-en-2-yl)phenyl)isonicotinamide

¹H NMR (300 MHz, CDCl₃) δ 8.62-8.65 (m, 2H), 8.37 (bd, J=12.9 Hz, 1H),8.02 (t, J=4.8 Hz, 1H), 7.32 (d, J=8.1 Hz 2H), 7.16 (d, J=8.1 2H), 1.96(s, 3H), 1.81 (s, 3H), 1.61 (s, 3H) ppm. ESMS calcd. (C17H17FN2O):284.1;found: 285.1(M+H).

Compound 14:3-methyl-N-(4-(2-methyl-1-phenylprop-1-enyl)phenyl)-isonicotinamide

¹H NMR (300 MHz, CDCl₃) δ 8.52 (s, 1H), 8.50 (d, J=4.9 Hz, 1H), 7.70(bs, 1H), 7.54 (d, J=8.1 Hz 2H), 7.31-7.26 (m, 2H), 7.21-7.11 (m, 5H),2.46 (s, 3H), 1.84 (s, 3H), 1.81 (s, 3H), 3.84 (s, 3H), 2.28 (s, 3H)ppm.

ESMS calcd. (C23H22N2O):342.2; found: 343.2 (M+H).

Compound 21:N-[4-(2-chloro-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide

To the solution of 2-Cyclohexen-1-one (500 mg, 5.2 mmol) in DCM (10 mL)was added pyridine (1.25 mL, 15.5 mmol) and phenylselenyl chloride (3.0g, 15.6 mmol). The reaction was stirred at room temperature overnight.The reaction solution was diluted with DCM (50 mL) and washed with H₂O(100 mL). The organic phase was separated, dried over Na₂SO₄, andchromatographied to give a (500 mg, 74%); To the solution of a (300 mg,2.3 mmol) in THF (15 mL) was added L-Selectride (1 M, 2.5 mL, 2.5 mmol)at −78° C. The solution was kept at this temperature for 30 minutesbefore PhNTf₂ (900 mg, 2.52 mmol) was added as solid in one portion. Thereaction was allowed to warm up to room temperature before NH₄Cl (40 mL)and ethyl acetate (50 mL) were added. The organic phase was collected,dried, concentrated, and chromatographied to afford triflate b (430 mg,71%); Compound 21 was prepared from triflate b following general Suzukicoupling procedure in 65% yield. ¹H NMR (300 MHz, CDCl₃) δ 7.70-7.59 (m,3 H), 7.44-7.15 (m, 3 H), 7.03-6.96 (m, 2 H), 2.51-2.45 (m, 2 H),2.41-2.36 (m, 2 H), 1.85-1.74 (m, 4 H); ESMS cacld (C₁₉H₁₆ClF₂NO):347.1; found: 348.1 (M+H).

Synthesis of Compounds 22, 23, 99, 100, 101:

Compound 99:N-[4-(2-ethyoxycarbonyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide

Following the general Suzuki coupling procedure Compound 99 was preparedin 61% yield. ¹H NMR (300 MHz, CDCl₃) δ 8.11 (s, 1 H), 7.55-7.34 (m, 3H), 7.12-7.01 (m, 2 H), 6.998-6.92 (m, 2 H), 3.91 (q, J=7.2 Hz, 2 H),2.36-2.30 (m, 4 H), 1.80-1.64 (m, 4 H), 0.96 (t, J=7.2 Hz, 3 H); ESMScacId (C₂₂H₂₁F₂NO₃): 385.2; found: 386.1 (M+H).

Compound 22:N-[4-(2-hydroxymethyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide

To the solution of Compound 99 (645 mg, 1.67 mmol) in THF (10 mL) wasadded LAH (320 mg, 8.4 mmol) at room temperature. After 10 min, thereaction was added 1N NaOH (5 mL) and H₂O (10 mL) and extracted withethyl acetate (EtOAc) (30 mL). The organic phase was collected, driedand concentrated. Column chromatography afforded Compound 22 (485 mg,85%). ¹H NMR (300 MHz, CDCl₃) δ 7.80 (s, 1 H), 7.59-7.56 (m, 2 H),7.45-7.35 (m, 1 H), 7.17-7.13 (m, 2 H), 7.13-6.94 (m, 2 H), 3.95 (s, 2H), 2.31-2.21 (m, 4 H), 1.78-1.64 (m, 4 H); ESMS cacld (C₂₀H₁₉F₂NO₂):343.1; found: 344.1 (M+H).

Compound 100:N-[4-(2-formyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide

To the solution of Compound 22 (55 mg, 0.16 mmol) in DCM (4 mL) wasadded Dess-Martin reagent (100 mg, 0.24 mmol). The solution was stirredat room temperature for 20 min before it was concentrated andchromatographed to afford Compound 100 (42 mg, 78%). ¹H NMR (300 MHz,CDCl₃) δ 9.52 (s, 1 H), 7.68-7.65 (m, 3 H), 7.47-7.41 (m, 1 H), 7.25 (d,J=8.4 Hz, 2 H), 7.02 (t, J=8.1 Hz, 2 H), 2.55-2.51 (m, 2 H), 2.37-2.31(m, 2 H), 1.79-1.71 (m, 4 H); ESMS cacld (C₂₀H₁₇F₂NO₂): 341.1; found:342.1 (M+H).

Compound 101:N-[4-(2-vinyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide

To the solution of Ph₃PCH₃Br (75 mg, 0.21 mmol) in THF (4 mL) was addedsodium hexamethyidisilazane (NaHMDS) (1 N, 0.21 mL, 0.21 mmol) at −78°C. After stirring at this temperature for 30 min, Compound 100 (70 mg,0.21 mmol) was added. The reaction solution was allowed to warm up toroom temperature and stirred overnight. The solution was quenched withNH₄Cl (20 mL) and extracted with EtOAc (30 mL). The organic portion wascollected, dried and concentrated. Column chromatography affordedCompound 101 (42 mg, 60%). ¹H NMR (300 MHz, CDCl₃) δ 7.63-7.51 (m, 3 H),7.45-7.38 (m, 1 H), 7.26-7.15 (m, 2 H), 7.04-6.97 (m, 2 H), 6.45 (dd,J=17.4 and 11.1 Hz, 1 H), 5.14 (d, J=17.4 Hz, 1 H), 4.86 (d, J=11.4 Hz,1 H), 2.37-2.29 (m, 4 H), 1.79-1.72 (m, 4 H); ESMS cacld (C₂₁H₁₉F₂NO):339.1; found: 340.1 (M+H).

Compound 23:N-[4-(2-oxazol-5-yl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide

The solution of Compound 100 (60 mg, 0.17 mmol), tosylmethylisocyanide(38 mg, 0.19 mmol) and K₂CO₃ (50 mg, 0.36 mmol) in MeOH (5 mL) wereheated at 90° C. for 40 min before it was filtered and concentrated. Theresidue was dissolved in EtOAc (10 mL) and H₂O (10 mL). The organicphase was collected, dried and concentrated. Column chromatographyafforded Compound 23 (47, 65%). ¹H NMR (300 MHz, CDCl₃) δ 7.64-7.59 (m,4 H), 7.46-7.40 (m, 1 H), 7.12 (d, J=8.7 Hz, 2 H), 7.01 (t, J=8.1 Hz, 2H), 6.21 (s, 1 H), 2.49-2.40 (m, 4 H), 1.84-1.76 (m, 4 H); ESMS cacid(C₂₂H₁₈F₂N₂O₂): 380.1; found: 381.1 (M+H).

Compound 24:N-[4-(2-oxazol-5-yl-cyclohexen-1-yl)-phenyl]-3-fluoroisonicotinamide

A mixed solution of Compound 102 (0.93 mmol) in methanol (4 mL) is addedtosylmethyl isocyanide (200 mg, 1.02 mmol) and K₂CO₃ (260 mg, 1.88mmol). The reaction is stirred at room temperature for 5 min beforeheated to 80° C. in the sealed tube. After 30 min, the solution iscooled to room temperature and concentrated. Column chromatographyafforded Compound 24.

¹H NMR (300 MHz, CDCl₃) δ 8.67-8.63 (m, 2 H), 8.41 (d, J=14.1 Hz, 1 H),8.03 (dd, J=6.3 and 5.1 Hz, 1 H), 7.65-7.60 (m, 3 H), 7.17-7.12 (m, 2H), 6.20 (s, 1 H), 2.50-2.40 (m, 4 H), 2.04-1.76 (m, 4 H); ESMS cacid(C₂₁H₁₈FN₃O₂): 363.1; found: 364.2 (M+H).

Compound 25:N-[4-(2-methyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide

To a solution of diisopropylamine (0.235 mL, 1.66 mmol) in Et₂O (15 mL)was added EtMgBr (3.0 M in Et₂O, 0.55 mL, 1.65 mmol) at 0° C. Thereaction was stirred at room temperature overnight. Then solution wascooled back to 0° C. before HMPA (0.64 mL, 3.7 mmol) and2-methylcyclohexanone (0.2 mL, 1.65 mmol) was added. After stirring atroom temperature for 6 hrs, PhNTf₂ (600 mg, 1.68 mmol) was added assolid in one portion. The resulting solution was stirred at roomtemperature for 12 hrs and refluxed at 40° C. for 5 hrs before it waswashed with 1 N HCl (15 mL), NaHCO₃ (15 mL), and brine (15 mL). Theorganic phase was dried and concentrated to give a crude product readyfor the next step. Compound 25 was obtained following the general Suzukicoupling procedure using the crude product in overall 43% yield. ¹H NMR(300 MHz, CDCl₃) δ 7.62-7.55 (m, 3 H), 7.44-7.40 (m, 1 H), 7.18-7.13 (m,2 H), 7.04-6.97 (m, 2 H), 2.24-1.56 (m, 11 H); ESMS cacld (C₂₀H₁₉F₂NO):327.1; found: 328.1 (M+H).

The following compounds were made by methods analogous to thosedescribed above.

Compound 26: 5-Methyl-pyrimidine-4-carboxylic acid[4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide

¹H NMR (300 MHz, CDCl₃) δ 10.06 (s, 1 H), 9.12 (s, 1 H), 8.76 (s, 1 H),7.69-7.65 (m, 2 H), 7.19-7.15 (m, 2 H), 2.79 (s, 3 H), 2.26-2.21 (m, 2H), 2.07 (brs, 2 H), 1.75-1.65 (m, 4 H), 1.57 (s, 3 H); ESMS cacld(C₁₉H₂₁N₃O): 307.2; found: 308.3 (M+H).

Compound 27: 4-Methyl-pyrimidine-5-carboxylic acid[4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide

¹H NMR (300 MHz, CDCl₃) δ 9.09 (s, 1 H), 8.72 (s, 1 H), 8.10 (s, 1 H),7.54 (d, J=8.4 Hz, 2 H), 7.15 (d, J=8.4 Hz, 2 H), 2.69 (s, 3 H), 2.20(brs, 2 H), 2.07 (brs, 2 H), 1.75-1.65 (m, 4 H), 1.56 (s, 3 H); ESMScacld (C₁₉H₂₁N₃O): 307.2; found: 308.3 (M+H).

Compound 28: 4-Chloro-thiazole-5-carboxylic acid[4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide

¹H NMR (300 MHz, CDCl₃) δ 8.84 (s, 1 H), 8.73 (s, 1 H), 7.56 (d, J=8.4Hz, 2 H), 7.18-7.15 (m, 2 H), 2.23 (brs, 2 H), 2.07 (brs, 2 H),1.75-1.67 (m, 4 H), 1.57 (s, 3 H);

ESMS cacld (C₁₇H₁₇ClN₂OS): 332.1; found: 333.2 (M+H).

Compound 29:N-[4-(2-ethyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide

¹H NMR (300 MHz, CDCl₃) δ 7.68 (s, 1 H), 7.58-7.54 (m, 2 H), 7.43-7.37(m, 1 H), 7.15-7.11 (m, 2 H), 7.02-6.95 (m, 2 H), 2.20-0.78 (m, 13 H);ESMS cacld (C₂₁H₂₁F₂NO): 341.2; found: 342.2 (M+H).

Compound 30:2-[4-(2,6-Difluoro-benzoylamino)phenyl]-cyclopent-1-enecarboxylic acidethyl ester

¹H NMR (300 MHz, CDCl₃) δ 7.80 (s, 1 H), 7.58 (d, J=8.7 Hz, 2 H),7.44-7.32 (m, 3 H), 7.03-6.96 (m, 2 H), 4.10 (q, J=7.2 Hz, 2 H),2.86-2.76 (m, 4 H), 2.04-1.94 (m, 4 H), 1.77 (t, J=7.2 Hz, 3 H); ESMScacld (C₂₁H₁₉F₂NO₃): 371.1; found: 372.1 (M+H).

Compound 31:2,6-Difluoro-N-[4-(2-hydroxymethyl-cyclopent-1-enyl)-phenyl]-benzamide

¹H NMR (300 MHz, CDCl₃) δ 7.63-7.59 (m, 3 H), 7.45-7.41 (m, 1 H),7.28-7.25 (m, 2 H), 7.00 (t, J=8.4 Hz, 2 H), 4.32 (d, J=4.2 Hz, 2 H),2.80-2.65 (m, 4 H), 2.02-1.92 (m, 2 H); ESMS cacld (C₁₉H₁₇F₂NO₂): 329.1;found: 330.1 (M+H).

Compound 32:2,6-Difluoro-N-[4-(2-formyl-cyclopent-1-enyl)-phenyl]-benzamide

¹H NMR (300 MHz, CDCl₃) δ 9.80 (s, 1 H), 8.06 (s, 1 H), 7.72-7.69 (m, 2H), 7.44-7.35 (m, 3 H), 6.99 (t, J=8.4 Hz, 2 H), 2.99-2.86 (m, 2 H),2.77-2.71 (m, 2 H), 2.08-1.96 (m, 2 H); ESMS cacld (C₁₉H₁₅F₂NO₂): 327.1;found: 328.1 (M+H).

Compound 33:2,6-Difluoro-N-[4-(2-vinyl-cyclopent-1-enyl)-phenyl]-benzamide

¹H NMR (300 MHz, CDCl₃) δ 7.71 (s, 1 H), 7.61 (d, J=7.5 Hz, 2 H),7.44-7.29 (m, 3 H), 7.03-6.96 (m, 2 H), 6.78 (dd, J=17.4 and 10.8 Hz, 1H), 5.20 (d, J=17.4 Hz, 1 H), 5.14 (d, J=10.8 Hz, 1 H), 2.83 (t, J=7.2Hz, 2 H), 2.68 (t, J=7.2 Hz, 2 H), 2.04-1.95 (m, 2 H); ESMS cacld(C₂₀H₁₇F₂NO): 325.1; found: 326.2 (M+H).

Compound 34:2,6-Difluoro-N-[4-(2-oxazol-5-yl-cyclopent-1-enyl)-phenyl]-benzamide

¹H NMR (300 MHz, CDCl₃) δ 8.11 (s, 1 H), 7.67-7.61 (m, 3 H), 7.43-7.30(m, 3 H), 6.97 (t, J=8.1 Hz, 2 H), 6.83 (s, 1 H), 2.86 (t, J=7.7 Hz, 4H), 2.12-2.02 (m, 2 H); ESMS cacld (C₂₁H₁₆F₂N₂O₂): 366.1; found: 367.1(M+H).

Compound 35:2,6-Difluoro-N-[4-(2-methoxycarbonyl-cyclohept-1-enyl)-phenyl]-benzamide

¹H NMR (300 MHz, CDCl₃) δ 7.82 (s, 1 H), 7.57-7.53 (m, 2 H), 7.46-7.39(m, 1 H), 7.16-7.13 (m, 2 H), 7.03-6.96 (m, 2 H), 3.43 (s, 3 H),2.62-2.53 (m, 4 H), 1.86-1.81 (m, 2 H), 1.68-1.60 (m, 4 H); ESMS cacld(C₂₂H₂₁F₂NO₃): 385.2; found: 386.2 (M+H).

Compound 36:2,6-Difluoro-N-[4-(2-hydroxymethyl-cyclohept-1-enyl)-phenyl]-benzamide

¹H NMR (300 MHz, CDCl₃) δ 7.59-7.56 (m, 3 H), 7.46-7.38 (m, 1 H),7.16-7.12 (m, 2 H), 7.05-6.98 (m, 2 H), 3.99 (d, J=5.7 Hz, 2 H),2.53-2.41 (m, 4 H), 1.85-1.80 (m, 2 H), 1.66-1.55 (m, 4 H); ESMS cacld(C₂₁H₂₁F₂NO₂): 357.2; found: 340.2 (M−OH).

Compound 37:2,6-Difluoro-N-[4-(2-formyl-cyclohept-1-enyl)-phenyl]-benzamide

¹H NMR (300 MHz, CDCl₃) δ 9.41 (s, 1 H), 7.86 (s, 1 H), 7.68-7.64 (m, 2H), 7.46-7.38 (m, 1 H), 7.25-7.21 (m, 2 H), 7.04-6.97 (m, 2 H),2.77-2.73 (m, 2 H), 2.63-2.59 (m, 2 H), 1.89-1.83 (m, 2 H), 1.75-1.67(m, 2 H), 1.56-1.48 (m, 2 H); ESMS cacld (C₂₁H₁₉F₂NO₂): 355.1; found:356.2 (M+H).

Compound 38:2,6-Difluoro-N-[4-(2-oxazol-5-yl-cyclohept-1-enyl)-phenyl]-benzamide

¹H NMR (300 MHz, CDCl₃) δ 7.71-7.58 (m, 4 H), 7.51-7.39 (m, 1 H),7.24-6.97 (m, 5 H), 2.68-2.52 (m, 4 H), 1.92-1.58 (m, 6 H); ESMS cacld(C₂₃H₂₀F₂N₂O₂): 394.2; found: 395.2 (M+H).

Compound 39:2,6-Difluoro-N-[4-(1-methoxycarbonyl-5-ethoxycarbonyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl]-benzamide

To the solution of h (500 mg, 1.75 mmol) in THF was added NaHMDS (1 M,2.7 mL, 2.7 mmol) at −78° C. After 30 min, PhNTf₂ (1.25 g, 3.5 mmol) wasadded as solid.

The reaction was allowed to warm up to room temperature before it wasquenched with NH₄Cl (20 mL). The organic phase was dried andconcentrated. The crude produce was used directly in the next Suzukistandard coupling step to afford Compound j (53% overall yield).

To the solution of Compound j (400 mg, 0.8 mmol) in DCM (4 mL) was addedTFA (1 mL). The reaction was stirred for 30 min at room temperaturebefore it was concentrated. The residue was dissolved 20 mL DCM andwashed with NaHCO₃ (20 mL). The organic phase was dried andconcentrated. To the solution of crude product in DCM (4 mL) was addedmethyl chloroformate (0.37 mL, 4.8 mmol) and TEA (0.67 mL, 0.48 mmol).The solution was stirred at room temperature for 1 hr before it wasconcentrated. Column chromatography afforded Compound 39 (290 mg, 79%).

¹H NMR (300 MHz, CDCl₃) δ 8.00 (s, 1 H), 7.64-7.56 (m, 2 H), 7.47-7.37(m, 1 H), 7.11 (d, J=8.7 Hz, 2 H), 6.97 (t, J=8.1 Hz, 2 H), 3.87 (q,J=7.2 Hz, 2 H), 3.71 (s, 3 H), 3.70-3.60 (m, 4 H), 2.72-2.61 (m, 4 H),0.91 (t, J=7.2 Hz, 3 H); ESMS cacld (C₂₄H₂₄F₂N₂O₅): 458.2; found: 459.4(M+H).

Compound 40:2,6-Difluoro-N-[4-(1-methoxycarbonyl-5-vinyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl]-benzamide

Compound 40 was synthesized from Compound 39 follow standard proceduresas shown in the synthesis below.

¹H NMR (300 MHz, CDCl₃) δ 7.83 (s, 1 H), 7.62-7.59 (m, 2 H), 7.44-7.26(m, 1 H), 7.12 (d, J=8.7 Hz, 2 H), 7.03-6.96 (m, 2 H), 6.38 (dd, J=17.4and 11.1 Hz, 1 H), 5.17 (d, J=17.4 Hz, 1 H), 4.93 (d, J=11.1 Hz, 1 H),3.71 (s, 3 H), 3.63 (brs, 4 H), 2.73-2.64 (m, 4 H); ESMS cacld(C₂₃H₂₂F₂N₂O₃): 412.2; found: 413.3 (M+H).

Synthesis of Compounds 41 and 42:

N-(4-(4-bromopyridin-3-yl)phenyl)-2,6-difluorobenzamide (e). To asolution of 4-Bromopyridine hydrochloride (500 mg, 2.57 mmol) in THF (15mL) was added LDA (2.0 N, 2.6 mL, 5.2 mmol) at −78° C. After 30 min, thesolution of ZnCl₂ (1 M in ether, 3.1 mL, 3.1 mmol) in THF (5 mL) wasadded slowly. The cold bath was removed and the solution was allowed towarm up room temperature. To this solution was added Pd(PPh₃)₄ (50 mg)and compound d (370 mg, 1.03 mmol). The solution was heated at 65° C.for 2 hrs before it was diluted with EtOAc (20 mL) and H₂O (10 mL). Theorganic phase was collected, dried and concentrated. Columnchromatography afforded Compound e (210 mg, 21%). ¹H NMR (300 MHz,(CD₃)₂SO) δ 10.99 (s, 1 H), 8.52 (s, 1 H), 8.40 (d, J=5.4 Hz, 1 H),7.84-7.78 (m, 3 H), 7.63-7.57 (m, 1 H), 7.47 (d, J=8.7 Hz, 2 H), 7.27(t, J=8.1 Hz, 2 H); ESMS cacld (C₁₈H₁₁BrF₂N₂O): 388.0; found: 389.1(M+H).

Compound 41:2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

The solution of Compound e (15 mg, 0.04 mmol), 2-thiazolylzinc bromidesolution (0.5 M, 0.2 mL, 0.1 mmol), and Pd(PPh₃)₂Cl₂ (5 mg) in THF (4mL) was heated in microwave synthesizer at 150° C. for 30 min. Thesolution was concentrated and chromatographied to give Compound f (13mg, 83%). To the solution of Compound f (13 mg, 0.033 mmol) in MeOH (2mL) was added benzyl bromide (BnBr) (0.05 mL, 0.4 mmol). After stirring60 min, the solvent was removed and the residue was washed with EtOAc (5mL) to remove BnBr. The resulting residue was dissolved in MeOH (4 mL)and added NaBH₄ (10 mg, 0.26 mmol). The solution was passed through ashort column of silica gel. The filtrate was concentrated and dissolvedin DCM (4 mL). After adding methyl chloroformate (0.1 mL), the solutionwas stirred overnight before it was concentrated and chromatographied togive Compound 41 (10 mg, 67%). ¹H NMR (300 MHz, CDCl₃) δ 7.79-7.62 (m, 4H), 7.52-7.38 (m, 1 H), 7.28-7.18 (m, 2 H), 7.09-6.98 (m, 3 H),4.26-4.18 (m, 2 H), 3.74 (s, 3 H), 2.95-2.88 (m, 2 H), 1.14-1.09 (m, 2H); ESMS cacld (C₂₃H₁₉F₂N₃O₃S): 455.1; found: 456.2 (M+H).

Compound 42:2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-isopropyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

To a solution of isopropylmagnesium chloride (2 M, 0.65 mL, 1.3 mmol) inEt₂O (5 mL) was added ZnCl₂ (1 M, 1.5 mL, 1.5 mmol) at 0° C. After 30min, Compound e (50 mg, 0.13 mmol) was added. The solution was stirredat room temperature for 2 hrs before it was quenched with NH₄Cl (5 mL).The mixture was diluted with EtOAc and the organic phase was collected,dried, and concentrated. Column chromatography afforded Compound g (25mg, 56%). From Compound g, Compound 42 was prepared following the sameprocedure as described for Compound 41 to give a 35% yield. ¹H NMR (300MHz, CDCl₃) δ 7.64-7.59 (m, 3 H), 7.45-7.38 (m, 1 H), 7.19-7.16 (m, 2H), 7.14-6.97 (m, 2 H), 4.06-3.99 (m, 2 H), 3.73 (s, 3 H), 3.62-3.58 (m,2 H), 2.22-2.18 (m, 2 H), 1.94-1.89 (m, 1 H), 1.57 (s, 6 H); ESMS cacld(C₂₃H₂₄F₂N₂O₃): 414.2; found: 415.3 (M+H).

General Procedure for Pyridinium Salt Formation:

A solution of pyridine (200 mg, 0.62 mmol) was dissolved indichloromethane (1.5 ml). Benzyl bromide (3 eq) was added and the roomtemperature solution was stirred for 24 hours. The solid was filteredand washed with cold dichloromethane to give pure pyridinium salt.

General Procedure for Reduction of Pyridinium Salt:

The pyridinium salt (crude) was dissolved in methanol and sodiumborohydride (113 mg, 3 eq) was added. This solution was warmed to 35° C.for 5 hours then cooled to room temperature. The methanol was removed,water and methylene chloride added, and extracted. The 150 mg (70%yield) of tetrahydropyridine was produced after column chromatography.

General procedure for Carbamate Formation:

The Compound 11 (31 mg, 0.074 mmol) was dissolved in methylene chloride(2 ml) at room temperature. Ethyl chloroformate (14 ul, 2 eq) was addedto the solution and the reaction was stirred for 3 hours. The solventwas removed and the crude mixture was purified by flash chromatographwith ethyl acetate/hexane to produce 28.4 mg (97% yield) of Compound 12.

General Procedure for Tetrahydropyridine Deprotection:

10% Palladium on carbon (10 mg, 10% w/w) was added to a methanolicsolution (1.5 ml) of Compound 51 (109 mg, 0.247 mmol). A ballon ofhydrogen was added to the top of the flask and thoroughly stirred for 1hour. After filtration pure Compound 43 was recovered (73 mg, 96%yield). No further purification was required.

General Procedure for Thiazole Amine Formation:

Compound 11 (725 mg, 1.73 mmol) was dissolved in methylene chloride (5ml) and cyanogen bromide (549 mg, 5.19 mmol) was added. This reactionwas stirred at room temperature for 1 hour then purified by flashchromatography. Pure cyanamide (415 mg, 68% yield) was isolated as awhite solid.

The cyanamide (55 mg, 0.01556 mmol) was dissolved in ethanol/ammonia (2ml, 2M). Hydrogen sulfide gas was then bubbled through the reactionsolution for 20 minutes at which time the bubbling was stopped, and thereaction was capped and allowed to stirred for 5 hours at roomtemperature. After completion, the solvent was removed and the thioureawas recrystallized from ethanol to remove yellow color.

The thiourea was then dissolved in anhydrous THF (5 ml) and the bromide(140 mg, 0.709 mmol) was added and refluxed for 5 hours. The reactionmixture was then quenched with sodium bicarbonate solution and dilutedwith ethyl acetate. After drying over magnesium sulfate, the compoundwas purified by flash chromotagraphy to yield 39 mg of pure Compound 44.The hydrochloride salt of Compound 44 was prepared by dissolvingCompound 44 in ethanol and excess HCl in ether was added. Solidprecipitated out of solution at −40° C. and was collected by filtrationto yield the hydrochloride salt (Compound 75).

Compound 45:N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide

Procedure: See General Procedure for Carbamate Formation

¹H NMR (300 MHz, CDCl₃) δ 8.67-8.65 (m, 2H), 8.48(d, J=12.6 Hz, 1H),8.02 (dd, J=5.1, 6.6 Hz, 1 H), 7.65(d, J=8.4 Hz, 2H), 7.20 (m, 2H),4.08-3.99 (m, 2H), 3.73 (s, 3H), 3.62-3.63 (m, 2H), 2.20-2.21 (m, 2H),1.64 (s, 3H), ppm

ESMS calcd. (C₂₀H₂O_(F)N₃O₃): 369.1; found: 370.2(M +H).

Compound 103:N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide

Procedure: See General Procedure for Carbamate Formation.

¹H NMR (300 MHz, CDCl₃) δ 8.57-8.55(m, 2H), 7.62(d, J=8.4 Hz, 2H), 7.36(d, J=4.8 Hz, 1H), 7.21(d, J=8.1 hz, 2H), 4.09-4.01 (m, 2H), 3.71 (s,3H), 3.57-3.65 (m, 2H), 2.50 (s, 3H), 2.19-2.22 (m, 2H), 1.64 (s, 3H)ppm

ESMS calcd. (C₂₁H₂₃N₃O₃): 365.2; found: 366.4(M+H).

Compound 47: 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide

Procedure: See General Procedure for Carbamate Formation.

ESMS calcd. (C₁₉H₂₂N₄O₃S): 386.1; found: 387.3(M+H).

Compound 48:N-[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide

Procedure: See General Procedure for Carbamate Formation.

ESMS calcd. (C₂₂H₂₅N₃O₃): 379.2; found: 380.1(M+H).

Compound 49:2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

Procedure: See General Procedure for Carbamate Formation.

¹H NMR (300 MHz, CDCl₃) δ 7.63(d, J=8.4 Hz, 2H), 7.46-7.38 (m, 1H), 7.20(d, J=8.4 Hz, 2H), 7.01(t, J=8.1 Hz, 2H), 4.07-4.06(m, 2H), 3.72 (s,3H), 3.60-3.63 (m, 2H), 2.21-2.20 (m, 2H), 1.64 (s, 3H)ppm

ESMS calcd. (C₂₁H₂₀F₂N₂O₃): 386.1; found: 387.1(M+H).

Compound 50:N-[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide,hydrochloride

Procedure: See General Procedure for Carbamate Formation.

¹H NMR (300 MHz, DMSO) δ 8.84 8.79 (m, 2H), 7.91 (s, 1H), 7.74 (d, J=8.7Hz, 2H), 7.22(d, J=8.7 Hz, 2H), 4.07 (q, J=6.9 Hz, 2H), 3.99 (s, 2H),3.55-3.52 (m, 2H), 2.47 (s, 3H), 2.16 (s, 2H), 1.61 (s, 3H), 1.20 (t,J=7.2 Hz, 3H)ppm ESMS calcd. (C₂₂H₂₆ClN₃O₃): 415.2; found: 380.2(M−Cl).

Compound 51:N-[4-(1-benzyloxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide

Procedure: See General Procedure for Carbamate Formation.

ESMS calcd. (C₂₇H₂₇N₃O₃): 441.2; found: 442.1 (M+H).

Compound 52: N-{4-[1-(4-nitro-phenyloxycarbonyl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide

Procedure: See General Procedure for Carbamate Formation.

¹H NMR (300 MHz, CDCl₃) δ 8.67-8.63 (m, 2H), 8.48(d, J=12.6 Hz, 1H),8.27-8.21 (m, 2H) 8.02 (dd, J=5.1, 6.6 Hz, 1 H), 7.67-7.61 (m, 2H),7.35-7.29 (m, 2H), 7.24-7.20 (m, 2H), 4.24-4.21(m, 1H), 4.19-4.17 (m,1H), 3.86-3.70 (m, 2H), 2.36-2.29 (m, 2H), 1.64 (s, 3H), ppm

ESMS calcd. (C₂₅H₂₁FN₄O5): 476.1; found: 476.2(M+H).

Compound 53:N-[4-(1-allyloxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide

Procedure: See General Procedure for Carbamate Formation.

¹H NMR (300 MHz, CDCl₃) δ 8.66-8.62 (m, 2H), 8.46 (d, J=10.5 Hz, 1H),8.01 (t, J=5.9 Hz, 1H), 7.65 (d, J=9.2 Hz, 2H), 7.27-7.19 (m, 2H),6.02-5.89 (m, 1H), 5.35-5.20 (m, 2H), 4.63-4.61 (m, 2H), 4.08 (m, 2H),3.66-3.62 (m, 2H), 2.22-2.20 (m, 2H), 1.64 (s, 3H) ppm

ESMS calcd. (C₂₂H₂₂FN₃O₃): 395.2; found: 395.2(M+H).

Compound 54:2,6-Difluoro-N-[4-(1-allyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide

Procedure: See General Procedure for Carbamate Formation.

ESMS calcd. (C₂₃H₂₂F2N₂O₃): 412.2; found: 412.3(M+H).

Compound 55:2,6-Difluoro-N-[4-(1-phenyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide

Procedure: See General Procedure for Carbamate Formation.

ESMS calcd. (C₂₆H₂₂F₂N₂O₃): 448.2; found: 449.2(M+H).

Compound 56:2,6-Difluoro-N-[4-(1-cyano-3-ethoxycarbonyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide

Procedure: General Procedure for Thiazole Amine Formation.

ESMS calcd. (C₂₂H₁₉F₂N₃O₃): 411.1; found: 412.1(M+H).

Compound 57:N-[4-(1-cyano-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, J=2.7 Hz, 1H), 8.66 (dd, J=1.5, 4.8Hz, 1H), 8.40(d, J=14.1 Hz, 1H), 8.04 (dd, J=5.1, 6.6 Hz, 1H), 7.68-7.65(m, 2H), 7.20-7.17 (m, 2H), 3.85 (dd, J=2.1, 3.9 Hz, 2H), 3.40 (t, J=5.7Hz, 2H), 2.3-2.36 (m, 2H), 1.65 (s, 3H) ppm

ESMS calcd. (C₁₉Hl₁₇FN₄O): 336.1; found: 337.1(M+H).

Compound 58:2,6-Difluoro-N-[4-(1-cyano4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, CDCl₃) δ7.66-7.60 (m, 3H), 7.50-7.40 (m, 1H), 7.13 (d,J=8.1 Hz, 2H), 7.02 (t, J=7.0 Hz, 2H), 3.85-3.84 (m, 2H), 3.39 (t, J=5.7Hz, 2H), 2.30-2.37 (m, 2H), 1.65 (s, 3H) ppm

ESMS calcd. (C₂₀H₁₇F₂N₃O): 353.1; found: 354.1(M+H).

Compound 59:N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, CDCl₃) δ 8.56(s, 1H), 8.54(d, J=5.1 Hz, 1H), 7.46 (s,1H), 7.63(d, J=8.4 Hz, 2H), 7.35 (d, J=4.8 Hz, 1H), 7.26-7.17 (m, 2H),6.56 (d, J=3.6 Hz, 1H), 4.08-4.07 (m, 2H), 3.73 (t, J=6 Hz, 2H), 2.50(s, 3H), 2.31-2.36 (m, 2H), 1.68 (s, 3H)ppm

ESMS calcd. (C₂₂H₂₂N₄OS): 390.2; found: 391.1(M+H).

Compound 65:N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, DMSO) δ 8.68 (d, J=2.7 Hz, 1H), 8.66 (dd, J=1.2, 5.1Hz, 1H), 8.15 (d, J=13.1 Hz, 1H), 8.05 (dd, J=4.8, 6.6 Hz, 1H), 7.67 (d,J=8.4 Hz, 2H), 7.29-7.22(m, 3H), 6.58 (d, J=3.9 Hz, 1H), 4.10-4.08 (m,2H), 3.75 (t, J=6.0 Hz, 2H), 2.39-2.36(m, 2H), 1.68 (s, 3H)ppm. ESMScalcd. (C₂₁H₁₉FN₄OS 394.1; found: 395.2 (M+1).

Compound 97:2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyrimidin-2-yl]-benzamide

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, CDCl₃) δ 9.69(s, 1H), 8.88(s, 1H), 8.15 (d, J=1.81 Hz,1H), 7.52-7.42 (m, 1H), 7.21(d, J=3.6 Hz, 1H) 7.03(t, J=8.4 Hz, 2H),6.57 (d, J=3.9 Hz, 1H), 4.28-4.27 (m, 2H), 3.77 (t, J=5.7 Hz, 2H),2.45-2.40 (m, 2H), 1.83 (s, 3H) ppm ESMS calcd. (C₂₀H₁₇F₂N₅OS) 413.11;found: 414.2 (M+H).

Compound 98:2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyrimidin-2-yl]-benzamide,hydrochloride

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, CDCl₃) δ 9.68(s, 1H), 8.41(s, 2H), 7.56-7.46 (m, 1H),7.37 (d, J=4.5 Hz, 1H), 7.071(t, J=8.1 Hz, 2H) 6.70(d, J=4.5 Hz, 1 H),4.47 (m, 2H), 4.34 (m, 2H), 2.62 (m, 2H), 1.96 (s, 3H) ppm ESMS calcd.(C₂₀H₁₈ClF₂N₅OS) 449.09; found: 414.4 (M−Cl).

Compound 72:2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyridin-2-yl]-benzamide,hydrochloride

Procedure: General Procedure for Thiazole Amine Formation.

General Procedure for Substitution of Amine with Acid Chloride/SulfonylChloride:

Compound 43 (22 mg, 307.4) was dissolved in methylene chloride (1 ml) atroom temperature. Triethylamine (28 ul, 0.216 mmol) was added followedby ethylsulfonyl chloride (7.5 ul, 0.079 mmol). The mixture was stirredfor 1 hour. Column chromatography yielded 18 mg of pure Compound 60 in a63% yield.

Addition of an acid chloride is done in an analogous manner as thatdescribed for addition of a sulfonyl chloride.

Compound 60:N-[4-(1-ethanesulfonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide

Procedure: See Example of Substitution of Amine with AcidChloride/Sulfonyl Chloride.

¹H NMR (300 MHz, CDCl₃) δ 8.53-8.50 (m, 2H), 7.85-7.83 (m,1 H),7.64-7.61 (m, 2H), 7.34-7.18 (m, 3H), 3.93-3.92 (m, 2H), 3.49-3.48 (m,2H), 3.00-2.98 (m, 2H), 2.48 (s, 3H), 2.31-2.30 (m, 2H), 1.65 (s, 3H),1.39-1.34 (m, 3H),

ESMS calcd. (C₂₁H₂₅N₃O₃S): 399.2; found: 400.2(M+H).

Compound 61:N-[4-(1-phenylsulfonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide

Procedure: See Example of Substitution of Amine with AcidChloride/Sulfonyl Chloride.

¹H NMR (300 MHz, CDCl₃) δ 8.57-8.55(m, 2H), 7.80-7.77(m, 2H), 7.61-7.50(m, 5H), 7.35(d, J=5.1 Hz, 1H), 7.15 (d, J=8.1 Hz, 3H), 3.71-3.67 (m,2H), 3.27 (t, J=5.7 Hz, 2H), 2.49 (s, 3H), 2.31-2.27 (m, 2H), 1.58(s,3H)ppm ESMS calcd. (C₂₅H₂₅N₃O₃S): 447.2; found: 448.3(M+H).

Compound 62:2,6-Difluoro-N-[4-(1-acetyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

Procedure: See Example of Substituion of Amine with AcidChloride/Sulfonyl Chloride.

ESMS calcd. (C₂₁H₂₀F₂N₂O₂): 370.1; found: 371.1(M+H).

Compound 63:2,6-Difluoro-N-[4-(1-cyclopropylcarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

Procedure: See Example of Substituion of Amine with AcidChloride/Sulfonyl Chloride.

ESMS calcd. (C₂₃H₂₂F₂N₂O₂): 396.2; found: 397.3(M+H).

Compound 64:2,6-Difluoro-N-{4-[1-(pyridine-3-carbonyl)-cyclopropanecarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide

Procedure: See Example of Substituion of Amine with AcidChloride/Sulfonyl Chloride.

¹H NMR (300 MHz, CDCl₃) δ 8.71-8.70 (m, 2H), 7.91 (s, 1 H), 7.80-7.77(m, 1H), 7.69-7.66 (m, 2H), 7.58-7.50 (m, 1H), 7.46-7.33 (m, 2H),7.02-6.96 (m, 3H), 4.37(s, 1H), 4.06-3.95 (m, 2H), 3.58-3.54 (m, 1H),2.33-2.26 (m, 2H), 1.67 (s, 3H)ppm ESMS calcd. (C₂₅H₂₁F₂N₃O₂): 433.2;found: 434.2(M+H).

General Procedure for Palladium Amine Coupling:

Compound 104 (200 mg, 0.642 mmol) was dissolved in toluene/MeOH/H₂O (6ml/0.5 ml/1 ml) followed by 2-bromo-pyridine (101 mg 0.77 mmol), Pd (20mg, 10% w/w), heated to 170° C. for 1 hour. The solvent was removed andit was dissolved in methylene chloride and purified by flash column togive Compound 66 (20 mg, 8% yield).

Compound 66:N-[4-(1-pyridin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide

Procedure: General Procedure for Palladium Amine Coupling.

NMR (300 MHz, CDCl₃) δ8.67 (d, J=2.7 Hz, 1H), 8.65 (dd, J=1.2, 4.8 Hz,1H), 8.40(d, J=13.8 Hz, 1H), 8.21 (ddd, J=0.9, 1.8, 4.8 Hz, 1H), 8.04(dd, J=4.8, 6.6 Hz, 1H), 7.68-7.62 (m, 2H), 7.51-7.45 (m, 1H), 7.32-7.26(m, 1H), 6.66-6.58 (m, 2H), 4.09-4.06 (m, 2H), 3.83 (t, J=5.7 Hz, 2H),2.33 (s, 2H), 1.67 (s, 3H)ppm

ESMS calcd. (C₂₃H₂₁FN₄O): 388.2; found: 389.2(M+H).

General Procedure for Nucleophilic Coupling with Amine:

A solution of Compound 104 (166 mg, 0.761 mmol) and triethylamine (317ul, 2.23 mmol) and benzoxazole (234 mg, 1.52 mmol) were dissolved in THF(5 ml) and heated to 100° C. in microwave. The reaction mixture was thendissolved in methylene chloride and flash chromatographed with methylenechloride/methanol 1-10% to give Compound 68 (128 mg, 50% yield).

Compound 68:2,6-Difluoro-N-[4-(1-benzooxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

Procedure: General Procedure for Nucleophilic Coupling with Amine.

ESMS calcd. (C₂₆H₂₁F2N₃O₂): 445.2; found: 446.2(M+H).

Compound 69:N-[4-(1-cyclopropylmethyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide

Procedure: General Procedure for Nucleophilic Coupling with Amine.

ESMS calcd. (C₂₂H₂₄FN₃O): 365.2; found: 366.3(M+H)

General Synthesis for Oxazole Amine:

To Compound 58 (55 mg, 0.168 mmol) in methylene chloride (2 ml) wasadded 2,2-dimethoxyethanol (35.5 mg, 0.335 mmol) followed bytosylsulfonic acid (95.6 mg, 0.503 mmol). This reaction mixture wasstirred at room temperature for 25 min. After neutralizing the reactionand washing with water, the solvent was removed and dissolved inmtheylene chloride. After heating in microwave to 120° C. for 15 min andpurifying by flash chromatography, 16 mg (26% yield) of Compound 70 wasisolated.

Compound 70:2,6-Difluoro-N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

Procedure: General Synthesis for Oxazole Amine

¹H NMR (300 MHz, CDCl₃) δ 7.69 (s, 1H), 7.61 (d, J=8.1 Hz, 2H),7.55-7.40 (m, 1H), 7.15-7.22 (m, 2H), 7.01 (t, J=7.9 Hz, 2H), 6.82 (s,1H), 4.12 (s, 1H), 3.71 (t, J=5.7, 2H), 2.25-2.34 (m, 2H), 1.62 (s, 3H)ppm

ESMS calcd. (C₂₂H₁₉F₂N₃O₂): 395.1; found: 395.0(M+H).

Compound 71:N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide

Procedure: General Synthesis for Oxazole Amine

¹H NMR (300 MHz, CDCl₃) δ8.67 (d, J=2.7 Hz, 1H), 8.65 (d, J=3.9 Hz, 1H),8.40 (d, J=12.6 Hz, 1H), 8.05 (dd, J=4.8, 6.6 Hz, 1H), 7.66 (d, 8.1 Hz,2H), 7.27-7.19 (m, 3H), 6.84 (s, 1H), 4.13-4.12 (m, 2H), 3.72 (t, J=6.0Hz, 2H), 2.32-2.30 (m, 2H), 1.67 (s, 3H)ppm

ESMS calcd. (C₂₁H₁₉FN₄O₂): 378.1; found: 379.1(M+H).

Compound 73:2,6-Difluoro-N-[4-(1-thiocarbamoyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, CDCl₃) δ 7.73 (s, 1H), 7.64 (d, J=8.4 Hz, 7.47-7.39 (m,1H), 7.20 (d, J=8.7 Hz, 2H), 7.02 (t, J=8.1 Hz, 2H), 5.75 (s, 2H),4.28-4.20 (m, 2H), 4.15-4.03 (m, 2H), 2.37-2.30 (m, 2H), 1.68 (s, 3H),1.62 (s, 2H)ppm

ESMS calcd. (C₂₀H₁₉F₂N₃OS): 387.1; found: 388.1(M+H).

Compound 74:N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide,dihydrochloride

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, DMSO) δ 10.85 (s, 1H), 8.79 (s, 1H), 8.61 (d, J=5.1 Hz,1H), 7.78-7.70 (m, H), 7.48(dd, J=1.2, 3.9 Hz, 1H), 7.33 (d, J=7.5 Hz,2H), 7.12 (dd, J=1.5, 4.2 Hz, 1H), 4.40 (broad s, 2H), 4.26 (s, 2H),3.81-3.78 (m, 2H), 2.41 (s, 2H), 1.69 (s, 3H) ppm. ESMS calcd.(C₂₁H₂₁F₂N₄OS) 466.1; found: 396.2 (M−2C−Hl).

Compound 75:2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide,hydrochloride

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, CDCl₃) δ 8.40 (s, 1H), 8.09 (d, J=8.1 Hz, 2H),7.87-7.80 (m, 1H), 7.70-7.65 (m, 3H), 7.43 (t, J=7.8 Hz, 2H), 6.99 (d,J=3.6 Hz, 1 H), 4.53 (s, 2H), 4.40-4.20 (m, 1H), 3.80 (d, J=5.1 Hz, 1H),2.81 (s, 2H), 2.11 (s, 3H)ppm

ESMS calcd. (C₂₂H₂₀ClF₂N₃OS): 447.1; found: 412.1M−Cl).

Compound 76:2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, CDCl₃) δ 7.77(bs, 1H), 7.65(d, J=8.4 Hz, 2H), 7.48-7.38(m, 1H), 7.26-7.20 (m, 2H), 7.01(t, J=7.8 Hz, 2H) 6.55( d, J=3.6 Hz,1H), 4.07-4.06 (m, 2H), 3.74 (t, J=5.7, 2H), 2.35-2.37 (m, 2H), 1.67 (s,3H) ppm ESMS calcd. (C₂₂H₁₉F₂N₃OS) 411.1; found: 412.1 (M+H).

Compound 77: 5-Methyl-pyrimidine-4-carboxylic acid[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)phenyl]-amide

Procedure: General Procedure for Thiazole Amine Formation.

¹H NMR (300 MHz, CDCl₃) δ 10.12 (s, 1H), 9.14 (s, 1H), 8.79 (s, 1H),7.76-7.73 (m, 2H), 7.27-7.21 (m, 3H), 6.56 (d, J=3.6 Hz, 1H), 4.09-4.08(m, 2H), 3.74 (t, J=5.8 Hz, 2H), 2.80 (s, 3H), 2.50-2.60 (m, 2H), 2.62(s, 3H)ppm

ESMS calcd. (C₂₁H₂₁N₅OS): 391.1; found: 392.1(M+H).

Compound 78:2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-formyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

Procedure: General Procedure for Thiazole Amine Formation.

ESMS calcd. (C₂₂H₁₇F₂N₃O₂S): 425.1; found: 426.2(M+H).

Compound 79:2,6-Difluoro-N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide,hydrochloride

Procedure: General Synthesis for Oxazole Amine.

ESMS calcd. (C₂₂H₂₀ClF₂N₃O₂): 431.1; found: 396.2(M−Cl)

Compound 80:2,6-Difluoro-N-{4-[1-(4-methyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide

Procedure: General Synthesis for Oxazole Amine

¹H NMR (300 MHz, CDCl₃) δ 8.24 (s, 1H), 7.65-7.62 (m, 2H), 7.44-7.34 (m,1H), 7.19 (d, J=8.4H), 7.07-6.91 (m, 3H), 4.09-4.01 (m, 2H), 3.68-3.64(m, 2H), 2.29-2.28 (m, 2H), 2.04 (s, 3H), 1.65 (s, 3H)ppm

ESMS calcd. (C₂₃H₂₁F₂N₃O₂): 409.2; found: 410.2(M+H).

Compound 81: 5-Methyl-pyrimidine-4-carboxylic acid{4-[1-(4,5-dimethyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-amide

Procedure: General Synthesis for Oxazole Amine.

¹H NMR (300 MHz, CDCl₃) δ 9.12 (s, 1H), 8.78 (s, 1H), 7.71 (d, J=8.4 Hz,2H), 7.23 (d, J=8.4 Hz, 2H), 4.05-4.04 (m, 2H), 3.63 (t, J=5.7 Hz, 2H),2.79 (s, 3H), 2.28-2.29(m, 2H), 2.12 (s, 3H), 1.98 (s, 3H), 1.65 (s, 3H)

ESMS calcd. (C₂₃H₂₅N₅O₂): 403.2; found: 404.2(M+H).

Compound 82:2,6-Difluoro-N-{4-[1-(4,5-dimethyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide

Procedure: General Synthesis for Oxazole Amine

¹H NMR (300 MHz, CDCl₃) δ8.36 (s, 1H), 7.65 (d, J=8.7 Hz, 2H),7.44-7.34(m, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.99-6.64 (m, 2H), 4.03-4.02(m, 2H), 3.62 (t, 5.6 Hz, 2H), 3.48(dq, J=0.9, 7.2 Hz, 2H), 2.28-2.25(m, 2H), 2.09(s, 3H), 1.95 (s, 3H), 1.65 (s, 3H)ppm

ESMS calcd. (C₂₄H₂₃F₂N₃O₂): 423.2; found: 424.2(M+H).

Compound 83:2,6-Difluoro-N-[4-(1-pyrimidin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide

Procedure: General Procedure for Nucleophilic Coupling with Amine.

¹H NMR (300 MHz, CDCl₃) δ8.33-8.321 (m, 2H), 7.77 (s, 1H), 7.63 (d,J=8.1 Hz, 2H), 7.46-7.39 (m, 1H), 7.27-7.24 (m, 2H), 7.03-6.97 (m, 2H),6.48 (t, J=4.7 Hz, 1H), 4.36-4.35 (m, 2H), 4.10-3.98 (m, 2H), 2.30-2.29(m, 2H), 1.67 (s, 3H)ppm

ESMS calcd. (C₂₃H₂₀F₂N₄O): 406.2; found: 407.2(M+H).

General Tetrazole Synthesis:

A solution of DMF (15 ml) containing Compound 57 (400 mg, 1.13 mmol),ammonium chloride (294 mg, 5.5 mmol) and sodium azide (358 mg, 5.5 mmol)was heated to 100° C. for 3 hours. The solution was then cooled to roomtemperature and the DMF was removed on rotary evaporator. Methylenechloride was added followed by excess TMS-diazomethane and stirred for 5minutes. The reaction mixture was purified by flash chromotagraphy toyield a 3:1 mixture of Compound 85 and Compound 86. Overall (226 mg, 59%yield).

Compound 85:N-{4-[1-(1-methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide

Procedure: General Tetrazole Syntheis.

¹H NMR (300 MHz, CDCl₃) δ 8.62-8.71 (m, 2H), 8.42-8.38 (m, 1H),8.40-8.11 (m, 1H), 7.66 (d, J=8.1 Hz, 2H), 7.35-7.28 (m, 2H), 4.19 (s,3H), 4.11-4.09 (m, 2H), 3.73 (m, 2H), 2.35-2.29 (m, 2H), 1.63 (s, 3H)ppm

ESMS calcd. (C₂₀H₂₀FN₇O): 393.2; found: 394.3(M+H).

Compound 87:2,6-Difluoro-N-{4-[1-(2-methyl-2H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide

Procedure: General Tetrazole Syntheis

¹H NMR (300 MHz, CDCl₃) δ 7.77 (s, 1H), 7.65-7.61 (m, 2H), 7.47-7.38 (m,1H), 7.26-7.22 (m, 2H), 7.04-6.97 (m, 2H), 4.18 (s, 3H), 4.13-4.08 (m,2H), 3.72 (t, J=5.9 Hz, 2H), 2.30-2.35 (m, 2H), 1.66 (s, 3H)ppm

ESMS calcd. (C₂₁H₂₀F₂N₆O): 410.2; found: 411.2(M+H).

Compound 88:2,6-Difluoro-N-{4-[1-(1H-tetrazol-5-yl)4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide

Procedure: General Tetrazole Syntheis

¹H NMR (300 MHz, CDCl₃) δ8.02 (s, 1H), 7.91-7.88 (m, 1H), 7.55 (d, J=8.4Hz, 2H), 7.48-7.40 (m, 1H), 7.17 (d, J=8.7 Hz, 2H), 7.02 (t, J=8.3 Hz,2H), 4.00 (s, 2H), 3.76 (t, J=5.8 Hz, 2H), 2.35-2.33 (m, 2H), 1.67 (s,3H),ppm

ESMS calcd. (C₂₀H₁₈F₂N₆O): 365.4; found: 366.3(M+H).

Compound 89:2,6-Difluoro-N-{4-[1-(1-methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide

Procedure: General Tetrazole Syntheis

¹H NMR (300 MHz, CDCl₃) δ 7.78 (s, 1H), 7.64 (d, J=7.8 Hz, 2H),7.46-7.38 (m, 1H), 7.20 (d, J=8.1 Hz, 2H), 7.01 (t, J=8.1 Hz, 2H),3.99-3.98 (m, 2H), 3.92 (s, 3H), 3.55 (t, J=5.9 Hz, 2H), 2.39-2.38 (m,2H), 1.67 (s, 3H)ppm

ESMS calcd. (C₂₁H₂₀F₂N₆O): 410.2; found: 411.2(M+H).

Compound 90:N-[4-(1-pyrimidin-5-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide

Procedure: General Procedure for Amine Coupling.

ESMS calcd. (C₂₂H₂₀FN₅O): 389.2; found: 390.3(M+H).

Compound 91:2,6-Difluoro-N-[4-(1-thiazol-2-yl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide

Procedure: General Procedure for Thiazole Amine Formation.

ESMS calcd. (C₂₂H₁₉F₂N₃OS): 411.1; found: 412.2(M+H).

General Synthesis of Diaryl Olefin

A solution of benzhydrylidene-(4-bromo-phenyl)-amine (2.75 g, 8.18 mmol)in THF (15 ml) was cooled to −78° C. in dry ice/IPA bath. N-BuLi (4.7ml, 9 mmol) was slowly added and the solution became dark, followed bythe organolithium falling out of solution. After stirring for 20 minuesbenzaldehyde (1 ml, 9.82 mmol) was then added (neat) to the −78° C.reaction and allowed to slowly warm to 0° C. The reaction was quenchedwith water and the organic layer was separated and dried over sodiumsulfate. Solvent was then removed and ether was added. To the etherealsolution was added manganese dioxide(>2 g) as a black solid and stirredfor 20 hours. The reaction was filtered through a pad of celite andcollected the light yellow solution. The diaryl ketone was purified bycolumn chromatography to give a 79% yield. The diaryl ketone (2 g, 5.11mmol) was dissolved in 15 ml of THF and HCl (aq) (1 ml, 6N). Thereaction mixture was stirred at room temperature for 10 min and thenquenched with a saturated solution of sodium bicarbonate. Afterextraction with ether, the product was concentration and dissolved inmethylene chloride (25 ml). Triethylamine (1 g, 10.22 mmol) was addedalong with 2,5-diflurobenzoyl chloride (1 g, 6.13 mmol) at roomtemperature. After 30 minutes the reaction was quenched with sat NaHCO₃solution. The methylene chloride layer was concentrated and loaded on aflash column. 1.87 g of pure N-(4-benzoyl-phenyl)-2,6-difluoro-benzamidewas isolated.

N-(4-benzoyl-phenyl)-2,6-difluoro-benzamide (870 mg, 2.37 mmol) wasdissolved in THF and cooled to −50° C. in a dry ice/acetone bath. Theisopropyl magnesium chloride was added and stirred for 30 min thenwarmed to room temperature for 30 min. Quenched with 6N HCl (aq)solution and stirred for 30 min. 883 mg (95% yield) of Compound 92 wasisolated after a column chromatography.

Compound 92:2,6-Difluoro-N-[4-(2-methyl-1-phenyl-propenyl)-phenyl]-benzamide

Procedure: General Synthesis of Diaryl Olefin

ESMS calcd. (C₂₃H₁₉F₂NO): 363.1; found: 364.3(M+H).

Compound 93:2,6-Difluoro-N-{4-[2-methyl-1-(4-methoxy-phenyl)-propenyl]-phenyl}-benzamide

Procedure: General Synthesis of Diaryl Olefin

ESMS calcd. (C₂₄H₂₁F₂NO₂): 393.2; found: 394.2(M+H).

Compound 94:2,6-Difluoro-N-{4-[2-methyl-1-(3-methoxy-phenyl)-propenyl]-phenyl}-benzamide

Procedure: General Synthesis of Diaryl Olefin

ESMS calcd. (C₂₄H₂₁F₂NO₂): 393.2; found: 394.2(M+H).

Compound 95:2,6-Difluoro-N-{4-[2-methyl-1-(2-methoxy-phenyl)-propenyl]-phenyl}-benzamide

Procedure: General Synthesis of Diaryl Olefin

¹H NMR (300 MHz, CDCl₃) δ 7.66 (s, 1H), 7.52-7.47 (m, 2H), 7.40-7.30 (m,1H), 7.23-7.16 (m, 3H), 7.08 (dd, J=1.5, 7.5 Hz, 1H), 6.98-6.84 (m, 4H),3.71 (s, 3H), 1.84 (s, 3H), 1.66 (s, 3H)ppm

ESMS calcd. (C₂₄H₂₁F₂NO₂): 393.2; found: 394.2(M+H).

General Procedure for Acetate Formation from Carboxylic Ester:

The ester (50 mg, 0.0146 mmol) was reduced at 0° C.-RT with lithiumaluminum hydride(146 ul,1M solution in THF) in diethyl ether (5 ml.)After 30 min, the reaction was quenched with water and magnesiumsulfate. After filtering, the solvent was removed and the crude alcoholwas dissolved in methylene chloride (3 ml). Excess acetic anhydride andtriethylamine were added. After 3 hours the reaction was quenched withsodium bicarbonate solution and purified by flash chromatography toprovide 31 mg(59% yield) of Compound 96 as a 1.75:1 mixture of isomers.

Example 2 Inhibition of IL-2 Production

Jurkat cells were placed in a 96 well plate (0.5 million cells per wellin 1% FBS medium) then a test compound of this invention was added atdifferent concentrations. After 10 minutes, the cells were activatedwith PHA (final concentration 2.5 μg/mL) and incubated for 20 hours at37° C. under CO₂. The final volume was 200 μL. Following incubation, thecells were centrifuged and the supernatants collected and stored at −70°C. prior to assaying for IL-2 production. A commercial ELISA kit (IL-2Eli-pair, Diaclone Research, Besancon, France) was used to detectproduction of IL-2, from which dose response curves were obtained. TheIC₅₀ value was calculated as the concentration at which 50% of maximumIL-2 production after stimulation was inhibited versus a non-stimulationcontrol. Compound # IC₅₀ 1 84.0 nM 2 11.0 nM 3 9.0 nM 4 7.0 nM 5 13.9 nM6 68.0 nM 7 >1000 nM 8 95.0 nM 9 748.4 nM 10 >1000 nM 11 >1000 nM 1223.0 nM 13 382.0 nM 14 159.2 nM 15 >1000 nM 16 24.6 nM 17 >1000 nM18 >1000 nM 19 513.4 nM 20 >1000 nM 21 23.2 nM 22 721.0 nM 23 7.4 nM 2468.0 nM 25 7.2 nM 26 164.7 nM 27 38.9 nM 28 142.6 nM 29 17.4 nM 30 299.7nM 31 >1000 nM 32 >1000 nM 33 97.1 nM 34 20.5 nM 35 103.6 nM 36 >1000 nM37 774.2 nM 38 23.1 nM 39 380.2 nM 40 22.8 nM 41 308.2 nM 42 11.9 nM 4412.0 nM 45 248.3 nM 47 410.7 nM 48 155.7 nM 49 16.2 nM 50 176.9 nM 51152.8 nM 52 651.3 nM 53 81.3 nM 54 235.0 nM 55 941.0 nM 56 >1000 nM57 >1000 nM 58 >1000 nM 59 48.9 nM 60 228.6 nM 61 163.8 nM 62 431.4 nM63 181.5 nM 64 962.0 nM 65 7.7 nM 66 42.1 nM 68 95.3 nM 69 >1000 nM 7012.4 nM 71 44.0 nM 72 35.0 nM 73 456.3 nM 74 5.0 nM 75 11.0 nM 76 12.0nM 77 99.3 nM 78 226.8 nM 80 98.5 nM 81 >1000 nM 82 59.5 nM 85 44.1 nM90 126.0 nM 91 226.0 nM 92 43.8 nM 93 54.6 nM 94 138.1 nM 95 155.9 nM 96631.1 nM 97 14.0 nM 98 282.0 nM 99 282.3 nM 100 90.0 nM 101 11.0 nM 103149.9 nM

Inhibition of other cytokines, such as IL4, IL-5, IL-13, GM-CSF, TNF-α,and INF-γ, can be tested in a similar manner using a commerciallyavailable ELISA kit for each cytokine.

Example 3 Patch Clamp Studies of Inhibition of I_(CRAC) Current in RBLCells, Jurkat Cells, and Primary T Cells

In general, a whole cell patch clamp method was used to examine theeffects of a compound of the invention on a channel that mediatesI_(crac). In such experiments, a baseline measurement was establishedfor a patched cell. Then a compound to be tested was perfused (orpuffed) to cells in the external solution and the effect of the compoundon I_(crac) was measured. A compound that modulates I_(crac) (e.g.,inhibits) is a compound that is useful in the invention for modulatingCRAC ion channel activity.

1) RBL Cells

Cells

Rat basophilic leukemia cells (RBL-2H3) were grown in DMEM mediasupplemented with 10% fetal bovine serum in an atmosphere of 95% air/5%CO₂. Cells were seeded on glass coverslips 1-3 days before use.

Recording Conditions

Membrane currents of individual cells were recorded using the whole-cellconfiguration of the patch clamp technique with an EPC10 (HEKAElectronik, Lambrecht, Germany). Electrodes (2-5 MΩ in resistance) werefashioned from borosilicate glass capillary tubes (Sutter Instruments,Novato, Calif.). The recordings were done at room temperature.

Intracellular Pipette Solution

The intracellular pipette solution contained Cs-Glutamate 120 mM; CsCl20 mM; CsBAPTA 10 mM; CsHEPES 10 mM; NaCl 8 mM; MgCl₂ 1 mM; IP3 0.02 mM;pH=7.4 adjusted with CsOH. The solution was kept on ice and shieldedfrom light before the experiment was preformed.

Extracellular Solution

The extracellular solution contained NaCl 138 mM; NaHEPES, 10 mM; CsCl10 mM; CaCl₂ 10 mM; Glucose 5.5 mM; KCl 5.4 mM; KH₂PO₄ 0.4 mM;Na₂HPO₄.H₂O 0.3 mM at pH=7.4 adjusted with NaOH.

Compound Treatment

Each compound was diluted from a 10 mM stock in series using DMSO. Thefinal DMSO concentration was always kept at 0.1%.

Experimental Procedure

I_(CRAC) currents were monitored every 2 seconds using a 50 msecprotocol, where the voltage was ramped from −100 mV to +100 mV. Themembrane potential was held at 0 mV between the test ramps. In a typicalexperiment, the peak inward currents would develop within 50-100seconds. Once the I_(CRAC) currents were stabilized, the cells wereperfused with a test compound in the extracellular solution. At the endof an experiment, the remaining I_(CRAC) currents were then challengedwith a control compound (SKF96365, 10 μM) to ensure that the currentcould still be inhibited.

Data Analysis

The I_(CRAC) current level was determined by measuring the inwardcurrent amplitude at −80 mV of the voltage ramp in an off-line analysisusing MATLAB. The I_(CRAC) current inhibition for each concentration wascalculated using peak amplitude in the beginning of the experiment fromthe same cell. The IC₅₀ value and Hill coefficient for each compound wasestimated by fitting all the individual data points to a single Hillequation.

Results

The table below shows the concentration of a compound of the inventionwhich inhibits 50% of the I_(CRAC) current in RBL cells. As can be seenfrom the data in the table, a representative compound of the inventioninhibit I_(CRAC) current at concentration of 100 nM. Compound NumberIC₅₀ 2 100 nM SKF96365  4 μM

2) Jurkat Cells

Cells

Jurkat T cells are grown on glass coverslips, transferred to therecording chamber and kept in a standard modified Ringer's solution ofthe following composition: NaCl 145 mM, KCl 2.8 mM, CsCl 10 mM, CaCl₂ 10mM, MgCl₂ 2 mM, glucose 10 mM, HEPES.NaOH 10 mM, pH 7.2.

Extracellular Solution

The external solution contains 10 mM CaNaR, 11.5 mM glucose and a testcompound at various concentrations.

Intracellular Pipette Solution

The standard intracellular pipette solution contains: Cs-glutamate 145mM, NaCl 8 mM, MgCl₂ 1 mM, ATP 0.5 mM, GTP 0.3 mM, pH 7.2 adjusted withCsOH. The solution is supplemented with a mixture of 10 mM Cs-BAPTA and4.3-5.3 mM CaCl₂ to buffer [Ca²⁺]i to resting levels of 100-150 nM.

Patch-Clamp Recordings

Patch-clamp experiments are performed in the tight-seal whole-cellconfiguration at 21-25° C. High-resolution current recordings areacquired by a computer-based patch-clamp amplifier system (EPC-9, HEKA,Lambrecht, Germany). Sylgard®-coated patch pipettes typically haveresistances between 2-4 MΩ after filling with the standard intracellularsolution. Immediately following establishment of the whole-cellconfiguration, voltage ramps of 50 ms duration spanning the voltagerange of −100 to +100 mV are delivered from a holding potential of 0 mVat a rate of 0.5 Hz over a period of 300 to 400 seconds. All voltagesare corrected for a liquid junction potential of 10 mV between externaland internal solutions. Currents are filtered at 2.3 kHz and digitizedat 100 μs intervals. Capacitive currents and series resistance aredetermined and corrected before each voltage ramp using the automaticcapacitance compensation of the EPC-9.

Data Analysis

The very first ramps before activation of I_(CRAC) (usually 1 to 3) aredigitally filtered at 2 kHz, pooled and used for leak-subtraction of allsubsequent current records. The low-resolution temporal development ofinward currents is extracted from the leak-corrected individual rampcurrent records by measuring the current amplitude at −80 mV or avoltage of choice.

Compounds of the invention are expected to inhibit I_(CRAC) current inJurkat cells.

3) Primary T Cells

Preparation of Primary T Cells

Primary T cells are obtained from human whole blood samples by adding100 μL of RosetteSep® human T cell enrichment cocktail to 2 mL of wholeblood. The mixture is incubated for 20 minutes at room temperature, thendiluted with an equal volume of PBS containing 2% FBS. The mixture islayered on top of RosetteSep® DM-L density medium and then centrifugedfor 20 minutes at 1200 g at room temperature. The enriched T cells arerecovered from the plasma/density medium interface, then washed with PBScontaining 2% FBS twice, and used in patch clamp experiments followingthe procedure described for RBL cells.

Compounds of the invention are expected to inhibit I_(CRAC) current inhuman primary T cells.

Example 4 Inhibition of Multiple Cytokines in Primary Human PBMCs

Peripheral blood mononuclear cells (PBMCS) are stimulated withphytohemagglutinin (PHA) in the presence of varying concentrations ofcompounds of the invention or cyclosporine A (CsA), a known inhibitor ofcytokine production. Cytokine production is measured using commerciallyavailable human ELISA assay kits (from Cell Science, Inc.) following themanufacturers instructions.

The compounds of the invention are potent inhibitors of IL-2, and areexpected to be potent inhibitors of IL-4, IL-5, IL-13, GM-CSF, INF-γ andTNF-α in primary human PBM cells. In addition, compounds of theinvention are not expected to inhibit the anti-inflammatory cytokine,IL-10.

Example 5 Compounds of the Invention are Potent Inhibitors ofDegranuylation in RBL Cells

Procedure:

The day before the assay is performed, RBL cells, that had been grown toconfluence in a 96 well plate, are incubated at 37° C. for at least 2hours. The medium is replaced in each well with 100 μL of fresh mediumcontaining 2 μLg/mL of anti-DNP IgE.

On the following day, the cells are washed once with PRS (2.6 mM glucoseand 0.1% BSA) and 160 μL of PRS was added to each well. A test compoundis added to a well in a 20 μL solution at 10× of the desiredconcentration and incubated for 20 to 40 minutes at 37° C. 20 μL of 10×mouse anti-IgE (10 μL/mL) is added. SKF96365 is used as a positivecontrol. Maximum degranulation typically occurs between 15 to 40 minutesafter addition of anti-IgE.

Results:

Compounds of the invention are expected to inhibit degranulation of RBLcells.

Example 6 Compounds of the Invention are Potent Inhibitors of Chemotaxisin T Cells

T-cell Isolation:

Twenty ml aliquots of heparinized whole blood (2 pig, 1 human) aresubjected to density gradient centrifugation on Ficoll Hypaque. Thebuffy coat layers representing peripheral blood mononuclear cells(PBMCs) containing lymphocytes and monocytes are washed once,resuspended in 12 ml of incomplete RPMI 1640 and then placed ingelatin-coated T75 culture flasks for 1 hr at 37° C. The non-adherentcells, representing peripheral blood lymphocytes (PBLs) depleted ofmonocytes, are resuspended in complete RPMI media and placed in looselypacked activated nylon wool columns that had been equilibrated with warmmedia. After 1 hr at 37° C., the non-adherent T cell populations areeluted by washing of the columns with additional media. The T cellpreparations are centrifuged, resuspended in 5 ml of incomplete RPMI,and counted using a hemocytometer.

Cell Migration Assay:

Aliquots of each T cell preparation are labeled with Calcien AM(TefLabs) and suspended at a concentration of 2.4×10⁶/ml inHEPES-buffered Hank's Balanced Salt Solution containing 1.83 mM CaCl₂and 0.8 mM MgCl₂, pH 7.4 (HHBSS). An equal volume of HHBSS containing 0,20 nM, 200 nM or 2000 nM of compound 1 or 20 nM EDTA is then added andthe cells are incubated for 30 min at 37° C. Fifty μl aliquots of thecell suspensions (60,000 cells) are placed on the membrane (pore size 5μm) of a Neuroprobe ChemoTx 96 well chemotaxis unit that had beenaffixed over wells containing 10 ng/ml MIP-1α in HHBSS. The T cells areallowed to migrate for 2 hr at 37° C., after which the apical surface ofthe membrane is wiped clean of cells. The chemotaxis units are thenplaced in a CytoFlour 4000 (PerSeptive BioSystems) and the fluorescenceof each well is measured (excitation and emission wavelengths of 450 and530 nm, respectively). The number of migrating cells in each well isdetermined from a standard curve generated from measuring thefluorescence of serial two-fold dilutions of the labeled cells placed inthe lower wells of the chemotaxis unit prior to affixing the membrane.

Results: Compounds of the invention are expected to be inhibitory to thechemotactic response of porcine T cells and in human T cells.

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting in any way.

From the foregoing description, it will be apparent that variations andmodifications may be made to the invention described herein. Suchembodiments are also within the scope of the following claims.

1. A method of inhibiting immune cell activation comprisingadministering to the cell a compound of structural formula (Ia):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; X₃, X₆ andX₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂; X₄ is CH₂, CHR₂,C(R₂)₂, or CHR₄, provided that when X₃ is NR₂, X₄ is CHR₄, and providedthat not more than one of X₃, X₆ or X₁₀ is NR₂; L₁ is a linker selectedfrom the group consisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—,—C(O)—NR—, —C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—,—C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—,—NRS(O)₂NR—, —NRC(R)₂NR—, ‘3CR═CR—, —C≡C—, —N=CR—, —CR=N—, —NR—N═CR—, or—CR═N—NR—; Y is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedmonocyclic aryl, or an optionally substituted heteroaryl; each Z isindependently selected from the group consisting of a lower alkyl, alower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano,nitro, or lower haloalkoxy; R is H or a lower alkyl; R₁ is H or asubstituent, provided that when R₁ is H, X₄ is CHR₄, and X₃ is NR₂; R₂,for each occurrence is, independently, a substituent, provided that R₂is not ═O or ═C(R₂₈)₂; R₄ is a substituent; R₈, for each occurrence, isindependently —H, a halo, an alkyl, —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or—C(O)NR₆R₇; wherein R₂₈, for each occurrence is, independently, H or asubstituent; n is 0, 1 or 2; and q is 0, 1 or 2, provided that when q is0 or 1, Y is not an optionally substituted alkyl; provided that when qis 1, Y is not a substituent represented by the following formula:

provided that the compound is not a compound represented by thefollowing structural formula:

wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and t is 0 or
 1. 2-3. (canceled) 4.A method of inhibiting cytokine production in a cell, comprisingadministering to the cell a compound of structural formula (Ia):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; X₃, X₆ andX₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂; X₄ is CH₂, CHR₂,C(R₂)₂, or CHR₄, provided that when X₃ is NR₂, X₄ is CHR₄, and providedthat not more than one of X₃, X₆ or X₁₀ is NR₂; L₁ is a linker selectedfrom the group consisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—,—C(O)—NR—, —C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—,—C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—,—NRS(O)₂NR—, —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or—CR═N—NR—; Y is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedmonocyclic aryl, or an optionally substituted heteroaryl; each Z isindependently selected from the group consisting of a lower alkyl, alower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano,nitro, or lower haloalkoxy; R is H or a lower alkyl; R₁ is H or asubstituent, provided that when R₁ is H, X₄ is CHR₄, and X₃ is NR₂; R₂,for each occurrence is, independently, a substituent, provided that R₂is not ═O or ═C(R₂₈)₂; R₄ is a substituent; R₈, for each occurrence, isindependently —H, a halo, an alkyl, —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or—C(O)NR₆R₇; wherein R₂₈, for each occurrence is, independently, H or asubstituent; n is 0, 1 or 2; and q is 0, 1 or 2, provided that when q is0 or 1, Y is not an optionally substituted alkyl; provided that when qis 1, Y is not a substituent represented by the following formula:

provided that the compound is not a compound represented by thefollowing structural formula:

wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and t is 0 or
 1. 5-7. (canceled) 8.The method of claim 4, wherein the cytokine is IL-2.
 9. A method ofmodulating an ion channel in a cell, wherein the ion channel is involvedin immune cell activation, comprising administering to the cell acompound of structural formula (Ia):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; X₃, X₆ andX₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂; X₄ is CH₂, CHR₂,C(R₂)₂, or CHR₄, provided that when X₃ is NR₂, X₄ is CHR₄, and providedthat not more than one of X₃, X₆ or X₁₀ is NR₂; L₁ is a linker selectedfrom the group consisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—,—C(O)—NR—, —C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—,—C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—,—NRS(O)₂NR—, —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or—CR═N—NR—; Y is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedmonocyclic aryl, or an optionally substituted heteroaryl; each Z isindependently selected from the group consisting of a lower alkyl, alower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano,nitro, or lower haloalkoxy; R is H or a lower alkyl; R₁ is H or asubstituent, provided that when R₁ is H, X₄ is CHR₄, and X₃ is NR₂; R₂,for each occurrence is, independently, a substituent, provided that R₂is not ═O or ═C(R₂₈)₂; R₄ is a substituent; R₈, for each occurrence, isindependently —H, a halo, an alkyl, —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or—C(O)NR₆R₇; wherein R₂₈, for each occurrence is, independently, H or asubstituent; n is 0, 1 or 2; and q is 0, 1 or 2, provided that when q is0 or 1, Y is not an optionally substituted alkyl; provided that when qis 1, Y is not a substituent represented by the following formula:

provided that the compound is not a compound represented by thefollowing structural formula:

wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and t is 0 or
 1. 10-11. (canceled)12. The method of claim 9, wherein the ion channel is aCa²⁺-release-activated Ca²⁺ channel (CRAC).
 13. A method of inhibitingT-cell and/or B-cell proliferation in response to an antigen, comprisingadministering to the cell a compound of structural formula (Ia):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; X₃, X₆ andX₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂; X₄ is CH₂, CHR₂,C(R₂)₂, or CHR₄, provided that when X₃ is NR₂, X₄ is CHR₄, and providedthat not more than one of X₃, X₆ or X₁₀ is NR₂; L₁ is a linker selectedfrom the group consisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—,—C(O)—NR—, —C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—,—C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—,—NRS(O)₂NR—, —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or—CR═N—NR—; Y is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedmonocyclic aryl, or an optionally substituted heteroaryl; each Z isindependently selected from the group consisting of a lower alkyl, alower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano,nitro, or lower haloalkoxy; R is H or a lower alkyl; R₁ is H or asubstituent, provided that when R₁ is H, X₄ is CHR₄, and X₃ is NR₂; R₂,for each occurrence is, independently, a substituent, provided that R₂is not ═O or ═C(R₂₈)₂; R₄ is a substituent; R₈, for each occurrence, isindependently —H, a halo, an alkyl, —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or—C(O)NR₆R₇; wherein R₂₈, for each occurrence is, independently, H or asubstituent; n is 0, 1 or 2; and q is 0, 1 or 2, provided that when q is0 or 1, Y is not an optionally substituted alkyl; provided that when qis 1, Y is not a substituent represented by the following formula:

provided that the compound is not a compound represented by thefollowing structural formula:

wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and t is 0 or
 1. 14-15. (canceled)16. A method for treating or preventing an immune disorder in a subjectin need thereof, comprising administering to the subject a compound ofstructural formula (Ia):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; X₃, X₆ andX₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂; X₄ is CH₂, CHR₂,C(R₂)₂, or CHR₄, provided that when X₃ is NR₂, X₄ is CHR₄, and providedthat not more than one of X₃, X₆ or X₁₀ is NR₂; L₁ is a linker selectedfrom the group consisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—,—C(O)—NR—, —C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—,—C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—,—NRS(O)₂NR—, —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, — NR—N═CR—, or—CR═N—NR—; Y is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedmonocyclic aryl, or an optionally substituted heteroaryl; each Z isindependently selected from the group consisting of a lower alkyl, alower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano,nitro, or lower haloalkoxy; R is H or a lower alkyl; R₁ is H or asubstituent, provided that when R₁ is H, X₄ is CHR₄, and X₃ is NR₂; R₂,for each occurrence is, independently, a substituent, provided that R₂is not ═O or ═C(R₂₈)₂; R₄ is a substituent; R₈, for each occurrence, isindependently —H, a halo, an alkyl, —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or—C(O)NR₆R₇; wherein R₂₈, for each occurrence is, independently, H or asubstituent; n is 0, 1 or 2; and q is 0, 1 or 2, provided that when q is0 or 1, Y is not an optionally substituted alkyl; provided that when qis 1, Y is not a substituent represented by the following formula:

provided that the compound is not a compound represented by thefollowing structural formula:

wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and t is or
 1. 17. (canceled) 18.The method of claim 16, wherein the disorder is selected from the groupconsisting of multiple sclerosis, myasthenia gravis, Guillain-Barre,autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia,autoimmune thrombocytopenia, temporal arteritis, anti-phospholipidsyndrome, vasculitides such as Wegener's granulomatosis, Behcet'sdisease, psoriasis, dermatitis herpetiformis, pemphigus vulgaris,vitiligo, Crohn's disease, ulcerative colitis, primary biliarycirrhosis, autoimmune hepatitis, Type 1 or immune-mediated diabetesmellitus, Grave's disease. Hashimoto's thyroiditis, autoimmuneoophoritis and orchitis, autoimmune disorder of the adrenal gland,rheumatoid arthritis, systemic lupus erythematosus, scleroderma,polymyositis, dermatomyositis, ankylosing spondylitis, and Sjogren'ssyndrome.
 19. A method for treating or preventing an inflammatorycondition in a subject in need thereof, comprising administering to thesubject a compound of structural formula (Ia):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; X₃, X₆ andX₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂; X₄ is CH₂, CHR₂,C(R₂)₂, or CHR₄, provided that when X₃ is NR₂, X₄ is CHR₄, and providedthat not more than one of X₃, X₆ or X₁₀ is NR₂; L₁ is a linker selectedfrom the group consisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—,—C(O)—NR—, —C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—,—C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—,—NRS(O)₂NR—, —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, — NR—N═CR—, or—CR═N—NR—; Y is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedmonocyclic aryl, or an optionally substituted heteroaryl; each Z isindependently selected from the group consisting of a lower alkyl, alower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano,nitro, or lower haloalkoxy; R is H or a lower alkyl; R₁ is H or asubstituent, provided that when R₁ is H, X₄ is CHR₄, and X₃ is NR₂; R₂,for each occurrence is, independently, a substituent, provided that R₂is not ═O or ═C(R₂₈)₂; R₄ is a substituent; R₈, for each occurrence, isindependently —H, a halo, an alkyl, —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or—C(O)NR₆R₇; wherein R₂₈, for each occurrence is, independently, H or asubstituent; n is 0, 1 or 2; and q is 0, 1 or 2, provided that when q is0 or 1, Y is not an optionally substituted alkyl; provided that when qis 1, Y is not a substituent represented by the following formula:

provided that the compound is not a compound represented by thefollowing structural formula:

wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and t is 0 or
 1. 20. (canceled) 21.The method according to claim 19, wherein the disorder is selected fromtransplant rejection, skin graft rejection, arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory bowel disease, ileitis, ulcerativecolitis, Barrett's syndrome, Crohn's disease; asthma, adult respiratorydistress syndrome, chronic obstructive airway disease; cornealdystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis,endophthalmitis; gingivitis, periodontitis; tuberculosis; leprosy;uremic complications, glomerulonephritis, nephrosis; sclerodermatitis,psoriasis, eczema; chronic demyelinating diseases of the nervous system,multiple sclerosis, AIDS-related neurodegeneration, Alzheimer's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis viral or autoimmuneencephalitis; autoimmune disorders, immune-complex vasculitis, systemiclupus and erythematodes; systemic lupus erythematosus (SLE);cardiomyopathy, ischemic heart disease hypercholesterolemia,atherosclerosis, preeclampsia; chronic liver failure, brain and spinalcord trauma, and cancer.
 22. A method for suppressing the immune systemof a subject in need thereof, comprising administering to the subject acompound of structural formula (Ia):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; X₃, X₆ andX₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂; X₄ is CH₂, CHR₂,C(R₂)₂, or CHR₄, provided that when X₃ is NR₂, X₄ is CHR₄, and providedthat not more than one of X₃, X₆ or X₁₀ is NR₂; L₁ is a linker selectedfrom the group consisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—,—C(O)—NR—, —C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—,—C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—,—NRS(O)₂NR—, —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or—CR═N—NR—; Y is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedmonocyclic aryl, or an optionally substituted heteroaryl; each Z isindependently selected from the group consisting of a lower alkyl, alower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano,nitro, or lower haloalkoxy; R is H or a lower alkyl; R₁ is H or asubstituent, provided that when R₁ is H, X₄ is CHR₄, and X₃ is NR₂; R₂,for each occurrence is, independently, a substituent, provided that R₂is not ═O or ═C(R₂₈)₂; R₄ is a substituent; R₈, for each occurrence, isindependently —H, a halo, an alkyl, —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or—C(O)NR₆R₇; wherein R₂₈, for each occurrence is, independently, H or asubstituent; n is 0, 1 or 2; and q is 0, 1 or 2, provided that when q is0 or 1, Y is not an optionally substituted alkyl; provided that when qis 1, Y is not a substituent represented by the following formula:

provided that the compound is not a compound represented by thefollowing structural formula:

wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and t is 0 or
 1. 23. (canceled) 24.A method of inhibiting mast cell degranulation, comprising administeringto the cell a compound of structural formula (Ia):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; X₃, X₆ andX₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂; X₄ is CH₂, CHR₂,C(R₂)₂, or CHR₄, provided that when X₃ is NR₂, X₄ is CHR₄, and providedthat not more than one of X₃, X₆ or X₁₀ is NR₂; L₁ is a linker selectedfrom the group consisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—,—C(O)—NR—, —C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—,—C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—,—NRS(O)₂NR—, —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or—CR═N—NR—; Y is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedmonocyclic aryl, or an optionally substituted heteroaryl; each Z isindependently selected from the group consisting of a lower alkyl, alower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano,nitro, or lower haloalkoxy; R is H or a lower alkyl; R₁ is H or asubstituent, provided that when R₁ is H, X₄ is CHR₄, and X₃ is NR₂; R₂,for each occurrence is, independently, a substituent, provided that R₂is not ═O or ═C(R₂₈)₂; R₄ is a substituent; R₈, for each occurrence, isindependently —H, a halo, an alkyl, —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or—C(O)NR₆R₇; wherein R₂₈, for each occurrence is, independently, H or asubstituent; n is 0, 1 or 2; and q is 0, 1 or 2, provided that when q is0 or 1, Y is not an optionally substituted alkyl; provided that when qis 1, Y is not a substituent represented by the following formula:

provided that the compound is not a compound represented by thefollowing structural formula:

wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and t is 0 or
 1. 25-26. (canceled)27. A method for treating or preventing an allergic disorder in asubject in need thereof, comprising administering to the subject acompound of structural formula (Ia):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; X₃, X₆ andX₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂; X₄ is CH₂, CHR₂,C(R₂)₂, or CHR₄, provided that when X₃ is NR₂, X₄ is CHR₄, and providedthat not more than one of X₃, X₆ or X₁₀ is NR₂; L₁ is a linker selectedfrom the group consisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—,—C(O)—NR—, —C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—,—C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—,—NRS(O)₂NR—, —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or—CR═N—NR—; Y is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedmonocyclic aryl, or an optionally substituted heteroaryl; each Z isindependently selected from the group consisting of a lower alkyl, alower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano,nitro, or lower haloalkoxy; R is H or a lower alkyl; R₁ is H or asubstituent, provided that when R₁ is H, X₄ is CHR₄, and X₃ is NR₂; R₂,for each occurrence is, independently, a substituent, provided that R₂is not ═O or ═C(R₂₈)₂; R₄ is a substituent; R₈, for each occurrence, isindependently —H, a halo, an alkyl, —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or—C(O)NR₆R₇; wherein R₂₈, for each occurrence is, independently, H or asubstituent; n is 0, 1 or 2; and q is 0, 1 or 2, provided that when q is0 or 1, Y is not an optionally substituted alkyl; provided that when qis 1, Y is not a substituent represented by the following formula:

provided that the compound is not a compound represented by thefollowing structural formula:

wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and t is 0 or
 1. 28. (canceled) 29.The method of claim 27, wherein the disorder is allergic rhinitis,sinusitis, rhinosinusitis, chronic otitis media, recurrent otitis media,drug reactions, insect sting reactions, latex reactions, conjunctivitis,urticaria, anaphylaxis reactions, anaphylactoid reactions, atopicdermatitis, asthma, or food allergies. 30-66. (canceled)
 67. A compoundof structural formula (Ia):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; X₃, X₆ andX₁₀ are each, independently, CH₂, CHR₂, C(R₂)₂, or NR₂; X₄ is CH₂, CHR₂,C(R₂)₂, or CHR₄, provided that when X₃ is NR₂, X₄ is CHR₄, and providedthat not more than one of X₃, X₆ or X₁₀ is NR₂; L₁ is a linker selectedfrom the group consisting of —NRC(R)₂—, —C(R)₂NR—, —C(O)—, —NR—C(O)—,—C(O)—NR—, —C(S)—, —C(NR₈)—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR₈)—,—C(NR₈)—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR₈)NR—, —S(O)₂NR—, —NRS(O)₂—,—NRS(O)₂NR—, —NRC(R)₂NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or—CR═N—NR—; Y is an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substitutedmonocyclic aryl, or an optionally substituted heteroaryl; each Z isindependently selected from the group consisting of a lower alkyl, alower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano,nitro, or lower haloalkoxy; R is H or a lower alkyl; R₁ is H or asubstituent, provided that when R₁ is H, X₄ is CHR₄, and X₃ is NR₂; R₂,for each occurrence is, independently, a substituent, provided that R₂is not ═O or ═C(R₂₈)₂; R₄ is a substituent; R₈, for each occurrence, isindependently —H, a halo, an alkyl, —OR₅, —NR₆R₇, —C(O)R₅, —C(O)OR₅, or—C(O)NR₆R₇; wherein R₂₈, for each occurrence is, independently, H or asubstituent; n is 0, 1 or 2; and q is 0, 1 or 2, provided that when q is0 or 1, Y is not an optionally substituted alkyl; provided that when qis 1, Y is not a substituent represented by the following formula:

provided that the compound is not a compound represented by thefollowing structural formula:

wherein R₂₉ is —NO₂ or —NHC(O)CH₂CN; and t is 0 or
 1. 68. The compoundof claim 67, wherein the compound is represented by structural formula(VII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein m is 0, 1, 2, 3,or
 4. 69. The compound of claim 68,wherein the compound is represented by structural formula (II):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 70. The compound of claim 69, wherein Y is selected from thegroup consisting of an optionally substituted phenyl, an optionallysubstituted pyridyl, an optionally substituted furyl, an optionallysubstituted thienyl, an optionally substituted pyrrolyl, an optionallysubstituted oxazolyl, an optionally substituted imidazolyl, anoptionally substituted indolizinyl, an optionally substituted thiazolyl,an optionally substituted isoxazolyl, an optionally substitutedpyrazolyl, an optionally substituted isothiazolyl, an optionallysubstituted pyridazinyl, an optionally substituted pyrimidinyl, anoptionally substituted pyrazinyl, an optionally substituted triazinyl,an optionally substituted triazolyl, an optionally substitutedthiadiazolyl, an optionally substituted pyrazinyl, an optionallysubstituted quinolinyl, an optionally substituted isoquniolinyl, anoptionally substituted indazolyl, an optionally substitutedbenzoxazolyl, an optionally substituted benzofuryl, an optionallysubstituted benzothiazolyl, an optionally substituted indolizinyl, anoptionally substituted imidazopyridinyl, an optionally substitutedisothiazolyl, an optionally substituted tetrazolyl, an optionallysubstituted benzoxazolyl, an optionally substituted benzothiazolyl, anoptionally substituted benzothiadiazolyl, an optionally substitutedbenzoxadiazolyl, an optionally substituted indolyl, an optionallysubstituted tetrahydroindolyl, an optionally substituted azaindolyl, anoptionally substituted imidazopyridyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted pyrrolo[2,3]pyrimidyl, an optionally substitutedpyridopyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl or anoptionally substituted benzo(b)thienyl.
 71. (canceled)
 72. The compoundof claim 69, wherein the compound is represented by structural formula(III):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 73. The compound of claim 72, wherein R₁ is selected from thegroup consisting of is a halo, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; and R₂is a halo, nitro, cyano, a haloalkyl, an optionally substituted alkyl anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, —C(O)NR₆R₇,—C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅,—C(S)SR₅—C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈ )SR₅, —S(O)_(p)R₅,—S(O)_(p)NR₆R₇, —P(O)(OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅)(SR₅,—P(S)(OR₅)(SR₅), —P(O)(SR₅)₂, or —P(S)(SR₅)₂.
 74. (canceled)
 75. Thecompound of claim 73, wherein the compound is represented by formula(IV):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₅ is CH or N; R₁₂ is a halo, a lower alkyl, a loweralkoxy, a haloalkyl, or a lower haloalkoxy; and R₁₃ is H, a halo, alower alkyl, a lower alkoxy, a haloalky, or a lower haloalkoxy. 76.(canceled)
 77. The compound of claim 69, wherein the compound isrepresented by structural formula (V):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 78. The compound of claim 77, wherein R₄ is selected from thegroup consisting of is a halo, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; and R₂is cyano, a haloalkyl, an optionally substituted alkyl an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, —C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅,—C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅, —C(S)SR₅, —C(NR₈)NR₆R₇,—C(NR₈)R₅, —C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅, —S(O)_(p)NR₆R₇,—P(O)(OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅(SR₅), —P(S)(OR₅(SR₅), —P(O)(SR₅)₂,or —P(S)(SR₅)₂.
 79. (canceled)
 80. The compound of claim 78, wherein thecompound is represented by structural formula (VI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₅ is CH or N; R₁₂ is a halo, a lower alkyl, a loweralkoxy, a haloalkyl, or a lower haloalkoxy; and R₁₃ is H, a halo, alower alkyl, a lower alkoxy, a haloalky, or a lower haloalkoxy. 81.(canceled)
 82. The compound of claim 67, wherein the compound isrepresented by formula (XVI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 83. The compound of claim 82, wherein R₁ is selected from thegroup consisting of is a halo, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₂ iscyano, a haloalkyl, an optionally substituted alkyl an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenvI, anoptionally substituted heterocyclyl, an optionally substituted aryl anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, —C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅,—C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅, —C(S)SR₅, —C(NR₈)NR₆R₇,—C(NR₈)R₅, —C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅, —S(O)_(p)NR₆R₇,—P(O)(OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅(SR₅), —P(S)(OR₅(SR₅), —P(O)(SR₅)₂,or —P(S)(SR₅)₂.
 84. (canceled)
 85. The compound of claim 83, wherein thecompound is represented by formula (XVII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₅ is CH or N; R₁₂ is a halo, a lower alkyl, a loweralkoxy, a haloalkyl, or a lower haloalkoxy; and R₁₃ is H, a halo, alower alkyl, a lower alkoxy, a haloalky, or a lower haloalkoxy. 86.(canceled)
 87. The compound of claim 67, wherein the compound isrepresented by formula (XVIII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein m is 0, 1, 2, 3, or
 4. 88. The compound of claim 87,wherein X₆ is CH₂ or CHR₂.
 89. The compound of claim 88, wherein thecompound is represented by formula (XIX):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 90. The compound of claim 89, wherein R₁ is selected from thegroup consisting of is a halo, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl.
 91. Thecompound of claim 90, wherein the compound is represented by formula(XX):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₅ is CH or N; R₁₂ is a halo, a lower alkyl, a loweralkoxy, a haloalkyl, or a lower haloalkoxy; and R₁₃ is H, a halo, alower alkyl, a lower alkoxy, a haloalky, or a lower haloalkoxy. 92.(canceled)
 93. The compound of claim 87, wherein X₆ is NR₂.
 94. Thecompound of claim 93, wherein the compound is represented by formula(XXI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 95. The compound of claim 94, wherein R₁ is selected from thegroup consisting of is a halo, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; and R₂is cyano, a haloalkyl, an optionally substituted alkyl an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, —C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅,—C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅, —C(S)SR₅, —C(NR₈)NR₆R₇,—C(NR₈)R₅, —C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅, —S(O)_(p)NR₆R₇,—P(O)OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅)(SR₅), —P(S)(OR₅)(SR₅), —P(O)(SR₅)₂,or —P(S)(SR₅)₂.
 96. (canceled)
 97. The compound of claim 95, wherein thecompound is represented by formula (XXII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₅ is CH or N; R₁₂ is a halo, a lower alkyl, a loweralkoxy, a haloalkyl, or a lower haloalkoxy; and R₁₃ is H, a halo, alower alkyl, a lower alkoxy, a haloalky, or a lower haloalkoxy. 98.(canceled)
 99. The compound of claim 67, wherein the compound isrepresented by formula (XXIII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein m is 0, 1, 2, 3, or
 4. 100. The compound of claim 99,wherein R₁ is selected from the group consisting of is a halo, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; and R₂ is cyano, a haloalkyl, an optionallysubstituted alkyl an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,—C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇, —C(S)R₅, —C(S)OR₅,—C(S)SR₅, —C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈)OR₅, —C(NR₈)SR₅, —S(O)_(p)R₅,—S(O)_(p)NR₆R₇, —P(O)OR₅)₂, —P(S)(OR₅)₂, —P(O)(OR₅)(SR₅),—P(S)(OR₅(SR₅), —P(O)(SR₅)₂, or —P(S)(SR₅)₂.
 101. (canceled)
 102. Thecompound of claim 100, wherein the compound is represented by formula(XXIV):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₅ is CH or N; R₁₂ is a halo, a lower alkyl, a loweralkoxy, a haloalkyl, or a lower haloalkoxy; and R₁₃ is H, a halo, alower alkyl, a lower alkoxy, a haloalky, or a lower haloalkoxy. 103.(canceled)
 104. The compound of claim 67, wherein the compound isselected from the group consisting of:3-Fluoro-N-[4-(2-methyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;3-Methyl-N-[4-(2-methyl-5(R)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;3-Methyl-N-[4-(2-methyl-5(S)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;3-Fluoro-N-[4-(2-methyl-5(R)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;3-Fluoro-N-[4-(2-methyl-5(S)-isopropenyl-cyclohex-1-enyl)-pyridin-2-yl]-isonicotinamide;3-Methyl-N-[4-(2-methyl-5(R)-acetyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;N-[4-(1,4-dimethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-2,6-difluoro-benzamide;5-[4-(2,6-difluoro-benzoylamino)-phenyl]-4-methyl-2,4-dihydro-2H-pyridine-1-carboxylicacid ethyl ester;N-(4-((S)-5-((R)-1,2-dihydroxypropan-2-yl)-2-methylcyclohex-1-enyl)phenyl)-3-methylisonicotinamide;N-(4-(1,4-dimethyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide;N-(4-(1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide;Ethyl3-(4-(2,6-difluorobenzamido)phenyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate;N-(4-(1,5-Dimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide;Ethyl4-(4-(2,6-difluorobenzamido)phenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate;2,6-Difluoro-N-(4-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)benzamide;N-(4-Cyclohexenylphenyl)-3-fluoroisonicotinamide;N-(4-(1-benzyl-5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide;N-(4-cyclohexenylphenyl)-3-fluoroisonicotinamide;N-[4-(2-chloro-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;N-[4-(2-hydroxymethyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;N-[4-(2-oxazol-5-yl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;N-[4-(2-oxazol-5-yl-cyclohexen-1-yl)-phenyl]-3-fluoroisonicotinamide;N-[4-(2-methyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;5-Methyl-pyrimidine-4-carboxylic acid[4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide;4-Methyl-pyrimidine-5-carboxylic acid[4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide;4-Chloro-thiazole-5-carboxylic acid[4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide;N-[4-(2-ethyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;2-[4-(2,6-Difluoro-benzoylamino)phenyl]-cyclopent-1-enecarboxylic acidethyl ester;2,6-Difluoro-N-[4-(2-hydroxymethyl-cyclopent-1-enyl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(2-formyl-cyclopent-1-enyl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(2-vinyl-cyclopent-1-enyl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(2-oxazol-5-yl-cyclopent-1-enyl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(2-methoxycarbonyl-cyclohept-1-enyl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(2-hydroxymethyl-cyclohept-1-enyl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(2-formyl-cyclohept-1-enyl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(2-oxazol-5-yl-cyclohept-1-enyl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(1-methoxycarbonyl-5-ethoxycarbonyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(1-methoxycarbonyl-5-vinyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-isopropyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;N-[4-(4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide;N-[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;N-[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide,hydrochloride;N-[4-(1-benzyloxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;N-{4-[1-(4-nitro-phenyloxycarbonyl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;N-[4-(1-allyloxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;2,6-Difluoro-N-[4-(1-allyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(1-phenyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(1-cyano-3-ethoxycarbonyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;N-[4-(1-cyano-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;2,6-Difluoro-N-[4-(1-cyano-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;N-[4-(1-ethanesulfonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;N-[4-(1-phenylsulfonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;2,6-Difluoro-N-[4-(1-acetyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(1-cyclopropylcarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;2,6-Difluoro-N-{4-[1-(pyridine-3-carbonyl)-cyclopropanecarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;N-[4-(1-pyridin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;N-[4-(1-benzooxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;2,6-Difluoro-N-[4-(1-benzooxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;N-[4-(1-cyclopropylmethyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;2,6-Difluoro-N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyridin-2-yl]-benzamide,hydrochloride;2,6-Difluoro-N-[4-(1-thiocarbamoyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide,dihydrochloride;2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide,hydrochloride;2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;5-Methyl-pyrimidine-4-carboxylic acid[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide;2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-formyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;2,6-Difluoro-N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide,hydrochloride;2,6-Difluoro-N-{4-[1-(4-methyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;5-Methyl-pyrimidine-4-carboxylic acid{4-[1-(4,5-dimethyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-amide;2,6-Difluoro-N-{4-[1-(4,5-dimethyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;2,6-Difluoro-N-[4-(1-pyrimidin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;N-{4-[1-(1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;N-{4-[1-(1-methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;N-{4-[1-(2-methyl-2H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;2,6-Difluoro-N-{4-[1-(2-methyl-2H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;2,6-Difluoro-N-{4-[1-(1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;2,6-Difluoro-N-{4-[1-(1-methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;N-[4-(1-pyrimidin-5-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;2,6-Difluoro-N-[4-(1-thiazol-2-yl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyrimidin-2-yl]-benzamide;2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyrimidin-2-yl]-benzamide;or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 105. A pharmaceutical composition, comprising apharmaceutically acceptable carrier and a compound of claim
 67. 106. Thepharmaceutical composition of claim 105, further comprising one or moreadditional therapeutic agents.
 107. The pharmaceutical compositionaccording to claim 106, wherein the additional therapeutic agent isselected from the group consisting of immunosuppressive agents,anti-inflammatory agents and suitable mixtures thereof.
 108. Thepharmaceutical composition of claim 107, wherein the additionaltherapeutic agent is selected from the group consisting of steroids,non-steroidal anti-inflammatory agents, antihistamines, analgesics, andsuitable mixtures thereof.
 109. A compound represented by formula (XXV):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: A is —O—, —S—, —NR₁₁—, —CR^(c)═CR^(d)—, —N═CR^(c)—,—CR^(c)═N—, or —N═N—; W₁ and W₂ are each, independently, CR^(c) or N; Y₁is an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, or an optionallysubstituted heteroaryl; L₂ is a linker; R₁₁ is H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,—OR₅, —SR₅, —NR₆R₇, —C(O)NR₆R₇, —C(O)R₅, —C(O)OR₅, —C(O)SR₅, —C(S)NR₆R₇,—C(S)R₅, —C(S)OR₅, —C(S)SR₅, —C(NR₈)NR₆R₇, —C(NR₈)R₅, —C(NR₈)OR₅, or—C(NR₈)SR₅; R^(c) and R^(d), for each occurrence, are independently, H,an optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, cyano, nitro, halo, —OR₅, —SR₅, —NR₆R₇, —C(O)NR₆R₇,—NR₅C(O)R₅, —C(O)R₅, —C(O)OR₅, —OC(O)R₅, —C(O)SR₅, —SC(O)R₅, —C(S)NR₆R₇,—NR₅C(S)R₅, —C(S)R₅, —C(S)OR₅, —OC(S)R₅, —C(S)SR₅, —SC(S)R₅,—C(NR₈)NR₆R₇, —NR₅C(NR₈)R₅, —C(NR₈)R₅, —C(NR₈)OR₅, —OC(NR₈)R₅,—C(NR₈)SR₅, —SC(NR₈)R₅, —OC(O)OR₅, —OC(O)NR₆R₇, —NR₅C(O)OR₅,—NR₅C(O)NR₆R₇, —SC(O)OR₅, —SC(O)NR₆R₇, —SC(O)SR₅, —NR₅C(O)SR₅,—OC(O)SR₅, —OC(S)OR₅, —OC(S)N R₆R₇, —NR₅C(S)OR₅, —NR₅C(S)N R₆R₇,—SC(S)OR₅, —SC(S)NR₆R₇, —SC(S)SR₅, —NR₅C(S)SR₅, —OC(S)SR₅, —OC(NR₈)OR₅,—OC(NR₈)NR₆R₇, —NR₅C(NR₈)OR₅, —NR₅C(NR₈)NR₆R₇,—SC(NR₈)OR₅,—SC(NR₈)NR₆R₇, —SC(NR₈)SR₅, —NR₅C(NR₈)SR₅, —OC(NR₈)SR₅,—S(O)_(p)R₅, —S(O)_(p)NR₆R₇, —NR₅S(O)_(p)R₅, —NR₅S(O)NR₆R₇,—S(O)_(p)OR₅, —OS(O)_(p)R₅, or —OS(O)OR₅; R₅, for each occurrence, isindependently, H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₆ and R₇, for each occurrenceare, independently, H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; or R₆ and R₇ taken together withthe nitrogen to which they are attached are an optionally substitutedheterocyclyl or optionally substituted heteroaryl; R₈, for eachoccurrence, is independently —H, a halo, an alkyl, —OR₅, —NR₆R₇,—C(O)R₅, —C(O)OR₅, or —C(O)NR₆R₇; R₁₄, R₁₅, and R₁₆ are each,independently, an optionally substituted alkyl, an optionallysubstituted cycloalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted heterocycloalkyl, anoptionally substituted aryl, an optionally substituted aralkyl, anoptionally substituted heteroaryl, or an optionally substitutedheteroaralkyl; and p is 1 or 2, provided that the compound is not apolymer; provided that the compound is not represented by one of thefollowing formulas:

wherein R₃₀ is methyl or benzoyl. 110-112. (canceled)
 113. The compoundof claim 109, wherein the compound is represented by formula (XXVI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: X₁ and X₂ are, independently, CH, CZ, or N; Y₃ is anoptionally substituted aryl or an optionally substituted heteroaryl;each Z is independently selected from the group consisting of a loweralkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl,cyano, nitro, or lower haloalkoxy; and n is 0, 1, or
 2. 114. Thecompound of claim 113, wherein Y₃ is selected from the group consistingof an optionally substituted phenyl, an optionally substituted pyridyl,an optionally substituted furyl, an optionally substituted thienyl, anoptionally substituted pyrrolyl, an optionally substituted oxazolyl, anoptionally substituted imidazolyl, an optionally substitutedindolizinyl, an optionally substituted thiazolyl, an optionallysubstituted isoxazolyl, an optionally substituted pyrazolyl, anoptionally substituted isothiazolyl, an optionally substitutedpyridazinyl, an optionally substituted pyrimidinyl, an optionallysubstituted pyrazinyl, an optionally substituted triazinyl, anoptionally substituted triazolyl, an optionally substitutedthiadiazolyl, an optionally substituted pyrazinyl, an optionallysubstituted quinolinyl, an optionally substituted isoquniolinyl, anoptionally substituted indazolyl, an optionally substitutedbenzoxazolyl, an optionally substituted benzofuryl, an optionallysubstituted benzothiazolyl, an optionally substituted indolizinyl, anoptionally substituted imidazopyridinyl, an optionally substitutedisothiazolyl, an optionally substituted tetrazolyl, an optionallysubstituted benzoxazolyl, an optionally substituted benzothiazolyl, anoptionally substituted benzothiadiazolyl, an optionally substitutedbenzoxadiazolyl, an optionally substituted indolyl, an optionallysubstituted tetrahydroindolyl, an optionally substituted azaindolyl, anoptionally substituted imidazopyridyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted pyrrolo[2,3]pyrimidyl, an optionally substitutedpyridopyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl or anoptionally substituted benzo(b)thienyl.
 115. The compound of claim 1 14,wherein Y₃ is represented by one of the following structure:

wherein: X₅ and X₈ are each, independently, CH or N; X₇ is O or S; R₁₂is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lowerhaloalkoxy; and R₁₃ is H, a halo, a lower alkyl, a lower alkoxy, ahaloalky, or a lower haloalkoxy.
 116. The compound of claim 115, whereinR₁₄, R₁₅ and R₁₆ are each, independently, a lower alkyl.
 117. Thecompound of claim 116, wherein the compound is3-fluoro-N-(4-(3-methylbut-2-en-2-yl)phenyl)-isonicotinamide, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 118. The compound of claim 115, wherein: R₁₄ and R₁₆ are alower alkyl; and R₁₅ is an optionally substituted aryl.
 119. Thecompound of claim 118, wherein the compound is selected from the groupconsisting of:3-methyl-N-(4-(2-methyl-1-phenylprop-1-enyl)phenyl)-isonicotinamide;2,6-Difluoro-N-[4-(2-methyl-1-phenyl-propenyl)-phenyl]-benzamide;2,6-Difluoro-N-{4-[2-methyl-1-(4-methoxy-phenyl)-propenyl]-phenyl}-benzamide;2,6-Difluoro-N-{4-[2-methyl-1-(3-methoxy-phenyl)-propenyl]-phenyl}-benzamide;2,6-Difluoro-N-{4-[2-methyl-1-(2-methoxy-phenyl)-propenyl]-phenyl}-benzamide;2,6-Difluoro-N-[4-(1,2-dimethyl-3-acetoxy-propenyl)-phenyl]-benzamide,or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 120. The compound of claim 114, wherein the compound is2,6-Difluoro-N-[4-(1,2-dimethyl-3-acetoxy-propenyl)-phenyl]-benzamide,or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 121. A method of inhibiting immune cell activation comprisingadministering to the cell a compound of claim
 109. 122-123. (canceled)124. A method of inhibiting cytokine production in a cell, comprisingadministering to the cell a compound of claim
 109. 125-127. (canceled)128. The method of claim 124, wherein the cytokine is IL-2.
 129. Amethod of modulating an ion channel in a cell, wherein the ion channelis involved in immune cell activation, comprising administering to thecell a compound of claim
 109. 130-131. (canceled)
 132. The method ofclaim 129, wherein the ion channel is a Ca²⁺-release-activated Ca²⁺channel (CRAC).
 133. A method of inhibiting T-cell and/or B-cellproliferation in response to an antigen, comprising administering to thecell a compound of claim
 109. 134-135. (canceled)
 136. A method fortreating or preventing an immune disorder in a subject in need thereof,comprising administering to the subject an effective amount of acompound of claim
 109. 137. (canceled)
 138. The method of claim 136,wherein the disorder is selected from the group consisting of multiplesclerosis, myasthenia gravis, Guillain-Barre, autoimmune uveitis,autoimmune hemolytic anemia, pernicious anemia, autoimmunethrombocytopenia, temporal arteritis, anti-phospholipid syndrome,vasculitides such as Wegener's granulomatosis, Behcet's disease,psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo,Crohn's disease, ulcerative colitis, primary biliary cirrhosis,autoimmune hepatitis, Type 1 or immune-mediated diabetes mellitus,Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis andorchitis, autoimmune disorder of the adrenal gland, rheumatoidarthritis, systemic lupus erythematosus, scleroderma, polymyositis,dermatomyositis, ankylosing spondylitis, and Sjogren's syndrome.
 139. Amethod for treating or preventing an inflammatory condition in a subjectin need thereof, comprising administering to the subject an effectiveamount of a compound of claim
 109. 140. (canceled)
 141. The methodaccording to claim 139, wherein the disorder is selected from transplantrejection, skin graft rejection, arthritis, rheumatoid arthritis,osteoarthritis and bone diseases associated with increased boneresorption; inflammatory bowel disease, ileitis, ulcerative colitis,Barrett's syndrome, Crohn's disease; asthma, adult respiratory distresssyndrome, chronic obstructive airway disease; corneal dystrophy,trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis,endophthalmitis; gingivitis, periodontitis; tuberculosis; leprosy;uremic complications, glomerulonephritis, nephrosis; sclerodermatitis,psoriasis, eczema; chronic demyelinating diseases of the nervous system,multiple sclerosis, AIDS-related neurodegeneration, Alzheimer's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis viral or autoimmuneencephalitis; autoimmune disorders, immune-complex vasculitis, systemiclupus and erythematodes; systemic lupus erythematosus (SLE);cardiomyopathy, ischemic heart disease hypercholesterolemia,atherosclerosis, preeclampsia; chronic liver failure, brain and spinalcord trauma, and cancer.
 142. A method for suppressing the immune systemof a subject in need thereof, comprising administering to the subject aneffective amount of a compound of claim
 109. 143. (canceled)
 144. Amethod of inhibiting mast cell degranulation, comprising administeringto the cell a compound of claim
 109. 145-146. (canceled)
 147. A methodfor treating or preventing an allergic disorder in a subject in needthereof, comprising administering to the subject an effective amount ofa compound of claim
 109. 148. (canceled)
 149. The method of claim 147,wherein the disorder is allergic rhinitis, sinusitis, rhinosinusitis,chronic otitis media, recurrent otitis media, drug reactions, insectsting reactions, latex reactions, conjunctivitis, urticaria, anaphylaxisreactions, anaphylactoid reactions, atopic dermatitis, asthma, or foodallergies.
 150. A pharmaceutical composition, comprising apharmaceutically acceptable carrier and a compound of claim
 109. 151.The pharmaceutical composition of claim 150, further comprising one ormore additional therapeutic agents.
 152. The pharmaceutical compositionaccording to claim 151, wherein the additional therapeutic agent isselected from the group consisting of immunosuppressive agents,anti-inflammatory agents and suitable mixtures thereof.
 153. Thepharmaceutical composition of claim 152, wherein the additionaltherapeutic agent is selected from the group consisting of steroids,non-steroidal anti-inflammatory agents, antihistamines, analgesics, andsuitable mixtures thereof.